Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 18, 2026.

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

Guo Li, Yuan Tian, Wei-Guo Zhu

Frontiers in Cell and Developmental Biology · 2020 · Review · CC BY

doi:10.3389/fcell.2020.576946

Abstract

Genetic mutations and abnormal gene regulation are key mechanisms underlying tumorigenesis. Nucleosomes, which consist of DNA wrapped around histone cores, represent the basic units of chromatin. The fifth amino group (Nε) of histone lysine residues is a common site for post-translational modifications (PTMs), and of these, acetylation is the second most common. Histone acetylation is modulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), and is involved in the regulation of gene expression. Over the past two decades, numerous studies characterizing HDACs and HDAC inhibitors (HDACi) have provided novel and exciting insights concerning their underlying biological mechanisms and potential anti-cancer treatments. In this review, we detail the diverse structures of HDACs and their underlying biological functions, including transcriptional regulation, metabolism, angiogenesis, DNA damage response, cell cycle, apoptosis, protein degradation, immunity and other several physiological processes. We also highlight potential avenues to use HDACi as novel, precision cancer treatments.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

In the nuclei of eukaryotic cells, the entire genome of an organism is condensed into chromatin. The nucleosome is the basic unit of chromatin: it contains 147 DNA base pairs coiled around a core histone octamer, which includes histones H2A, H2B, H3 and H4. The additional linker histone H1 interacts with chromatin outside of the core octamer to regulate higher order chromatin structure. There are two major higher order structures: heterochromatin refers to condensed chromatin, and euchromatin refers to loosely packed chromatin that is more accessible to transcriptional regulators and RNA polymerase complexes. Thus, alteration and regulation of chromatin structure impacts gene expression by making certain genes more or less available for transcription.

The epigenome is comprised of modifications to chromatin, including DNA methylation and histone modifications. For example, DNA accessibility is regulated by nucleosome sliding or post-translational modifications (PTMs), which include phosphorylation, methylation and acetylation. These covalent modifications control the structure and function of chromatin through a number of regulators. These regulators can be broadly divided into “readers” (enzymes that bind to modifications and facilitate epigenetic activities), “writers”(enzymes that establish DNA methylation or histone modifications), and “erasers”(enzymes that remove these markers). As an example, acetylation occurs at the fifth NH2 (Nε) of histone lysine residues, and is read by the bromodomain-containing protein (BRD), written by histone acetyltransferases (HATs), and erased by histone deacetylases (HDACs).

The acetylation of lysine residues (Kac) on histone tails generates positive charges, which neutralize negatively charged DNA and the unwinding of tightly coiled heterochromatin. Histone acetylation can increase the inner pore space of chromatin from 20 nm to 60−100 nm, altering spatial distance and accessibility during interphase; it also ensures sufficient space for local transcriptional events, including initiation and elongation. Acetylation is of particular importance because the interaction between histones and chromatin is generally very stable, and interruption of this interaction requires a high concentration of NaCl or acetate. Notably, acetylation is often a necessary precursor to other modifications, such as phosphorylation, methylation and ubiquitylation.

Acetylation is controlled by two antagonistic enzyme families: HATs and HDACs. HDACs are expressed by various tumors, and are involved in vital chromosomal translocation-mediated oncogenic protein fusion and carcinogenic events. These enzymes were first revealed to remove acetyl groups from histones by Vincent Allfrey. The first HDAC that was discovered, HDAC1, was originally isolated by utilizing a microbe-derived cyclic tetrapeptide, Trapoxin, which inhibits histone deacetylation and induces cell-cycle arrest. Sequence homology-dependent HDACs were subsequently identified, and shown to be involved in major biological functions such as transcription, metastasis, autophagy, cell cycle, DNA damage repair, angiogenesis, stress responses and senescence.

Histone deacetylase inhibitors (HDACi) might be able to reverse the activation of tumor suppressor genes (TSG), and in this way inhibit the viability and malignant proliferation of tumor cells. The efficacy of HDACi treatment has been demonstrated in numerous clinical studies. This review discusses HDACs and their inhibitors in the context of potential cancer treatments.

Classifications of HDACs

According to their sequence similarities with yeast HDACs, 18 human HDACs have been identified and grouped into four classes. Class I HDACs include HDAC1, -2, -3, and -8. Class II HDACs are further divided into two subgroups: class IIa and class IIb. Class IIa includes HDAC4, -5, -7, and -9 and class IIb includes HDAC6 and -10. Class III, also known as the sirtuins (SIRTs), include SIRT1-7, and class IV contains only HDAC11. SIRTs are nicotinamide adenine dinucleotide (NAD+)-dependent enzymes, while the other three classes are Zinc cation (or Zn2+ ion)-dependent HDACs. Besides the deacetylase activity, a number of diverse enzymatic activities of HDACs are presented in Table 1 and the sequence characteristics of HDACs are presented in Figure 1.

Class I HDACs

Of class I HDACs, HDAC1, -2, and -3 catalytic activities depend on their respective co-repressor complexes. Based on the conserved structures and dimerization domains, HDAC1 and HDAC2 are often recruited to the same co-repressor complexes, including Mi-2/nucleosome remodeling deacetylase (NuRD), repressor element-1 silencing transcription co-repressor (RCOR1/CoREST), SWI-independent-3A (Sin3A) and mitotic deacetylase complex (MiDAC). HDAC3 associates with the nuclear receptor co-repressor (NCoR) and silencing mediator for retinoid or thyroid-hormone receptors (SMRT) to form co-repressors. The NCoR/SMRT complex provides a platform for the recruitment and activation of HDAC3 in the deacetylase-activating domain (DAD) of SMRT. Inositol phosphate, an intermolecular “glue”; binds to the interface between the co-repressors and HDAC catalytic domains, improving the catalytic activity of the HDACs in NuRD and NCoR/SMRT complexes. Particularly, the HDAC8 monomer accommodates substrates with a unique flexible L1 loop in its N-terminal region, which is absent in other HDACs. Therefore, this motif is likely to be conducive to the development of HDAC8-specific inhibitors. Furthermore, its crystal structure indicates that dimerization occurs at the binding interface between HDAC8 and its substrate.

Class II HDACs

All Class IIa HDACs include an extended N-terminal domain that contains conserved serine (Ser) residues and other motifs for localization and function. Based on these Ser residues, several kinases such as calcium/calmodulin-dependent protein kinase (CaMK), salt-inducible kinase (SIK) and members of microtubule affinity-regulating kinase (MARK/hPar-1) phosphorylate Class IIa HDACs, which facilitates HDACs nuclear export through chromosomal region maintenance 1 protein (CRM1) [also called exportin 1 (XPO1)]- or ankyrin repeat family A protein 2 (ANKRA2)-recognized nuclear export sequence (NES). For nuclear localization, all class IIa HDACs contain nuclear localization sequence (NLS). 14-3-3 protein inhibits the nuclear localization of these HDACs by blocking their interaction with importin α. The absence of 14-3-3 promotes HDAC4/5 nuclear localization, which also facilitates transcription repression by binding to HDAC3. Of note, Class IIa HDACs contains myocyte enhancer factor 2 (MEF2) binding sites. The phosphorylated kinases-induced exported HDACs dissociate with nuclear MEF2 family proteins that are response for differentiated gene expression. Nevertheless, Class IIa HDACs have significant weaker deacetylase activity compared to Class I. X-ray crystallography data have revealed that the catalytic pocket of histone deacetylase-like protein (HDLP) contains several key catalytic sites, such as histidine (His), aspartic acid (Asp) and tyrosine (Tyr). Class IIa HDACs have relatively low catalytic ability due to a substitution of asparagine to Asp on the Asp-His charge relay. Moreover, the catalytic Tyr is conserved in other HDACs except for class IIa enzymes, where the Tyr residue is replaced by His. Substitution of His back to Tyr at 976 recovers the enzymatic activity of class IIa HDACs.

Of the class IIb HDACs, HDAC6 is a microtubule-associated deacetylase that is predominantly localized in the cytoplasm. HDAC6 contains a microtubule-binding domain that promotes chemotactic cell motility; it also includes a double-tandem deacetylase domain and a serine-glutamine containing tetradecapeptide (SE14) repeats domain that is important for cytoplasmic anchoring. HDAC6 undergoes nuclear export via leucine-rich motifs that are recognized by CRM1/exportin1, and contains NLS at adjacent Kac sites in the N-terminal. HDAC6 also contains zinc-finger ubiquitin binding domains (ZnF-UBP, also called PAZ domain) that negatively regulate polyubiquitin chain turnover. Recently, two deacetylase domains of HDAC6 have been re-classified as catalytic domain 1 (CD1) and CD2: these domains confer differential substrate recognition.

HDAC10 is a polyamine deacetylase that preferentially catalyzes N8-acetylspermidine hydrolysis to generate acetate. It contains a leucine-rich domain, a deacetylase domain and an inactivity domain. Similar to class IIa HDACs, HDAC10 associates with HDAC2, HDAC3, SMRT, and NCOR2 to enhance transcriptional repression.

Class III HDACs

A total of seven NAD+-dependent class III HDACs, or SIRTs, have been identified in the cytoplasm, nucleus and mitochondria. SIRT1, which is distributed in the cytoplasm, mitochondria and the nucleus, has two CRM1-mediated NES and two NLS: it undergoes conformational shifts in response to adenosine triphosphate (ATP), which impedes its ability to interact with substrates in the C-terminal domain. SIRT2 is even more widely distributed than SIRT1, being found in the plasma membrane and cytoskeleton-associated organelles in addition to the cytoplasm, nucleus and mitochondria: it contains a CRM1-dependent NES and a putative leucine-rich NES. By contrast, SIRT3, SIRT4, and SIRT5 are primarily found in the mitochondria. SIRT3 has the capability to shuttle from the nucleus to the mitochondria via its mitochondrial localization sequence, which is also responsible for its mitochondrial deacetylation activity. Of note, these mitochondrial regulators transfer to the nucleus in response to DNA damage induced by etoposide treatment or ultraviolet (UV) irradiation. SIRT6 is widely distributed, being found in the nuclear plasma, the heterochromatin, the nucleolus, as well as the cytoplasm. SIRT6 has a slower catalytic rate than other active SIRTs on substrates because SIRT6 lacks the conserved, highly flexible NAD+-binding loop, and instead contains a stable single helix. Finally, SIRT7, predominantly locates in the nucleolus but also exists in the cytoplasm and is involved in mitochondrial function. Two sequences in the N-terminal and C-terminal regions of SIRT7 permit nuclear and nucleolar localization, respectively.

Class IV HDACs

HDAC11 is the exclusive member of the class IV HDACs. Recent studies have indicated that HDAC11 might predominantly be more involved in the fatty acylation of proteins compared to its weak deacetylation.

Here, we recapitulate the detailed distributions of all 18 HDACs in Table 2.

Biological Functions of HDACs

Histone deacetylases are expressed in different tumors: class I and II HDACs are considered to be general oncoproteins that interact with substrates and regulate gene expression to promote tumorigenesis and cancer development either individually or alongside with co-repressors. Paradoxically, SIRTs can serve as both oncoproteins and tumor suppressors. We list the demonstrated knockout (KO) or knockdown models of 18 HDACs (Table 2). Because of the diverse biological function of HDACs, it is not surprising that HDACi regimens influence many cellular processes, including those that contribute to cancer progression.

Transcription Modulators

Transcription factors (TFs) can either directly target DNA or undergo various PTMs to alter gene expression. In this manner, HDACs negatively modulate transcription through forming a complex with TFs or by directly regulating TF transcription. For instance, the v-myc avian myelocytomatosis viral oncogene homolog (Myc) is a well-characterized proto-oncogene that promotes tumorigenesis by directly recruiting and interacting with HDACs to regulate gene expression. Meanwhile, Myc acetylation is also modulated by HDACs either directly or indirectly. For example, SIRT2 stabilizes N-Myc and c-Myc proteins by deacetylating and repressing neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4), which mediates Myc ubiquitination and degradation. Consequently, the SIRT2-specific inhibitor thiomyristoyl (TM) promotes Myc ubiquitination and degradation. HDACi suberoylanilide hydroxamic acid (SAHA) and entinostat (also called MS-275) induce Myc acetylation at K323, downregulating Myc and accompanying with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) activation. Therapeutic regimens that target Myc suppression using HDACi combined with DNA demethylation reagents seems to have a notable effect on non-small cell lung cancer (NSCLC) through activating immune system.

p53 is a well-known TSG that is crucial for mediating gene expression: its activity is modulated by various PTMs. HDACs and SIRTs downregulate p53 activity to promote cancer cell survival in response to oxidative stress. Specifically, HDAC1, -2, and -3 all can induce p53 deacetylation that represses p53-mediated apoptosis. In addition, HDAC2 modulates p53 transcriptional activity through direct p53-DNA binding. p53 binds to DNA depending on its acetylation state at K373/K382 by p300. HDACi depsipeptide induces acetylation at K373/K382 by recruiting p300. This in turn promotes the expression of p21Cip1/Waf1 (encoded by cyclin dependent kinase inhibitor 1A, CDKN1A). Compared to wild type p53, HDAC deficiency reduces mutant p53 (mtp53) expression both at the mRNA and protein level. Besides the transcriptional regulation of mtp53, HDACs also modulate mtp53 protein stability. By inhibiting HDAC6, SAHA promotes the preferential degradation of mtp53 by downregulating heat shock protein 90 (HSP90) that suppresses p53 degradation via E3 murine double minute (MDM2) or carboxy terminus of HSP70-interacting protein (CHIP). Therefore, inducing mtp53 degradation by blocking HDAC6-HSP90 might represent a novel strategy to suppress oncogenesis in the future.

In addition to TFs, HDACs also modulate the activity of super enhancers (SEs). Enhancer RNAs (eRNAs) are short, non-coding RNA molecules that alter the transcription of target genes in cooperation with promoters. Trichostatin A (TSA) and SAHA reduce eRNA synthesis by inhibiting HSP90. MEF2D and HDAC4/9 form a corepressor to recognize intergenic regions. HDAC4/9 depleted cells show increased H3K27ac level around the gene transcriptional start sites where show the features of active enhancers within corresponded topologically associated domains (TAD). Class I-specific HDACi 4SC-202 globally increases both of H3K27ac and H3K4me3 levels around the TSS of genes, but notably decreases occupancy at proximal regions of TSS of genes such as SMAD family member 6 (SMAD6) and E2F transcription factor 8 (E2F8), which are associated with enhancer deactivation. Panobinostat and romidepsin alter the acetylation status of H3K27 by disrupting the SE topology in paired box 8 (PAX8). Largazole (a cyclic peptides similar to depsipeptide) preferentially disturbs SE-driven transcripts that are frequently associated with oncogenic activities.

Transcriptional Activation

Although HDACs generally function as gene silencers, they can also activate transcription. Besides the regulation of enhancers, a potential mechanism underlying this role includes the modulation of RNA polymerase II (RNAP2) by HDACs. HDACs participate in the crosstalk between RNAP2 C-terminal domain acetylation and phosphorylation. SIRT6 recruits and mono-ADP-ribosylates switch/sucrose non-fermenting (SWI/SNF) related, matrix associated, actin dependent regulator of chromatin subfamily c member 2 (SMARCC2/BAF170) to form active chromatin at the enhancer of heme oxygenase-1, which subsequently recruits RNAP2. SIRT6 can also bind p53 to effectively recruit RNAP2 to local promoters. SIRT6 deficiency mediates the activation of cyclin-dependent kinase 9 (CDK9) that can phosphorylate negative elongation factor (NELF) and mediate NELF release from RNAP2, facilitating the enrichment of TFs and RNAP2-related elongation factors to promote elongation of specific gene sets. Consistently, TSA and SAHA disturb RNAP2-mediated transcriptional elongation by promoting the association between RNAP2 and NELF. Moreover, high doses of largazole can cause RNAP2-mediated transcriptional pausing and cell death.

DNA Methylation and Deacetylation

DNA methylation and histone modification modulate transcription, either alone or cooperatively, by altering chromatin status. HDACs and their complexes are recruited to hyper-methylated DNA through methyl-CpG binding domain containing (MBD) protein (MeCP), which has transcriptional repression roles. To maintain DNA methylation, DNA (cytosine-5-)-methyltransferase 1 (DNMT1) binds to HDAC1 and HDAC2 to establish heritable transcriptional silencing. A number of major breakthroughs involving combinations of HDACi and DNA demethylation reagents [DNA methyltransferase inhibitors (DNMTi)] have occurred in the past two decades. The rationale underlying combined DNMTi and HDACi therapy lies in their synergistic effects on compacted chromatin. Dense methylation of CpG islands (CGI) is responsible for silencing genes, which can be reactivated by HDACi. In this scenario, TSA loosens the structure of chromatin and induces the expression of previously silenced genes in the presence of DNMTi. The combination of 5-aza-2’-deoxycytidine (5-Aza-CdR, decitabine, Dacogen, Otsuka) and either depsipeptide or TSA induces the expression of p21Cip/Waf1, p15 (CDKN2B/INK4B), p16 (CDKN2A/INK4B), and p19 (CDKN2D/INK4D). Depsipeptide and apicidin induce demethylation and re-activate silenced genes such as p16, GATA binding protein 4 (GATA4) and sal-like protein 3 (SALL3) by inhibiting DNMT1 binding to these gene promoters. In terms of the direct anti-tumor effects, DNMTi in combination with HDACi can provoke a durable, powerful clinical response in patients. Several combinational therapies present in regimen of reversing tumor immune evasion in NSCLC. Azacytidine plus ITF-2357 (givinostat) seems to be the most efficient strategy that augments antigen presentation machinery and interferon α/β (IFNα/β)-related immune gene activation, and mainly focuses on suppression of Myc-driven tumorigenesis. With their broad range of physiological functions in various tissues, the combined effects of HDACi and DMNTi hold substantial therapeutic promise going forward.

Synergetic Regulation of HDACs and Other Histone Modifiers

In addition to DNA methylation, HDACs also cooperate with other epigenetic modifiers. For example, lysine-specific demethylase 1 [LSD1, lysine demethylase 1A (KDM1A)] is responsible for removing mono- or di-methylation of H3K4, and represses transcription via the CoREST-HDACs complex. A dual inhibitor of HDAC and LSD1, corin, has been developed to suppress CoREST-HDACs and to coordinately increase H3K4me1, H3K27ac and H3K27me3. KDM2B induces H3K79 demethylation and transcriptional repression in a SIRT1-dependent manner. KDM4A modulates gene repression though a physiological interaction with the NCoR-HDAC3 complex. KDM5A directly associates with HDAC complexes to regulate H3K4me2/3. The H3K36me2 demethylase KDM8 increases H3/H4 acetylation and Cyclin A1 transcriptional activation by impeding HDAC1 recruitment.

Regarding histone lysine methyltransferases, HDAC3 modulates the H3K9ac/H3K9me3 transition in a suppressor of variegation 3-9 homolog 1 (SUV39H1, also called KMT1A)-dependent manner during the DNA damage response (DDR). SIRT1 regulates H3K9 methylation by deacetylating K266 in the Su(var)3-9, enhancer-of-zeste and trithorax (SET) domain of SUV39H1, thus increasing its activity during heterochromatin formation. While SIRT6 induces the monoubiquitination of cysteines (Cys) in the pre-SET domain of SUV39H1, removing SUV39H1 from IκBα negatively regulates the nuclear factor-kappaB (NF-κB) pathway. Depsipeptide decreases H3K9me2/3 expression by reducing the expression of SUV39H1 and G9A (also called KMT1C). SIRT2 binds and deacetylates PR-Set7/SET8/KMT5A at K90, and increases the H4K20me1 level. HDACs also interact with polycomb-group (PcG) proteins to reset chromatin remodeling and transcriptional repression. SIRT1 interacts with Set7/9 (also called KMT7), with several sites being methylated by Set7/9. In response to DNA damage, SIRT1-p53 binding is significantly enhanced in the presence of Set7/9 and this binding coincide with increased p53 acetylation at K382.

The BRD family proteins are readers of Kac. Class I HDACi 4SC-202, mocetinostat and entinostat induce increase of hundreds of gene expression, which are mostly enriched upon BRD4- and MYC-targeted TSS-proximal regions. p21 is activated by 4SC-202 to inhibit cell proliferation. Similarly, JQ1 cooperates with SAHA to inhibit the growth of pancreatic ductal adenocarcinoma (PDAC) by upregulating p57 (CDKN1C) that usually blocked by Myc. Besides, HDACs also interact with protein arginine methyltransferases (PRMTs) to regulate gene transcription. These findings all highlight the competition among the “readers”, “writers” and “erasers” at acetylated histones and non-histones, and may provide additional, novel and combination epigenetic approaches for cancer therapy in the future (Figure 2).

Metabolism

Various kinases and metabolic pathways form a complex network with epigenetic co-repressors to dynamically regulate metabolic flux and enzyme activity; aberrations in these processes can result in tumorigenesis and cancer progression. Metabolism can affect protein acetylation by altering the concentration of NAD+ and acetyl-CoA. In turn, HDACs also mediate metabolic reprogramming in cancer cells.

Cancer cells are often characterized by their strong glycolytic activity, with aerobic glycolytic activity being preferred for tumor energy metabolism. Increased glycolysis is associated with the abnormal regulation of glycolytic enzymes and other glucose metabolism pathways. Class II HDACs induce trans-repression of gluconeogenic enzymes from the cytoplasm to the nucleus in an HDAC3-dependent manner, and mediate the deacetylation and activation of the forkhead box class O (FoxO) family in the nucleus. SIRT2 deacetylated isocitrate dehydrogenase 1 (IDH1) at K224 and promotes IDH1 enzymatic activity. The hypoacetylated IDH1 converts isocitrate into α-ketoglutarate in the tricarboxylic acid (TCA) cycle to inhibit liver metastases of colorectal cancer (CRC). Pyruvate kinase (PKM2) promotes tumorigenesis by regulating oncogene expression and proliferation pathway activation in HDAC3-dependent way. SIRT6 can directly interact with and deacetylate PKM2, resulting in its nuclear export via exportin 4 and suppression of PKM2-related oncogenic functions. Conversely, SIRT3 and SIRT6 also act as tumor suppressors, restricting aerobic glycolysis in cancer cells through destabilization of hypoxia inducible factor 1 subunit alpha (HIF-1α) and inhibition of glycolytic kinases, respectively. p53 directly binds and activates SIRT6 to regulate gluconeogenesis by mediating the nuclear exclusion and deacetylation of FoxO1.

The fatty acylation of proteins has a vital role in membrane synthesis, vesicle transport, protein-membrane interaction, cell signaling and localization. HDACs regulate fatty acylation during cancer progression. For example, HDAC8 performs lysine de-fatty-acylation functions. The HDAC8-selective inhibitor PCI-34051 also increases overall fatty acylation levels in Jurkat cells. HDAC11 has a relatively low effect on acetyl groups, but efficiently catalyzes dodecanoylated and myristoylated peptides. Compared with acetyl peptides, some HDACs have higher catalytic efficiency on acyl groups (see Table 1). HDAC11 efficiently removes acyl groups on the surface of serine hydroxymethyltransferase 2α (SHMT2α), causing SHMT2α dissociation from the late endosome/lysosome. This effect leads to type I interferon receptor chain 1 (IFNαR1) polyubiquitylation and degradation, as well as downregulation of IFN signaling. HDAC11-specific inhibitors, such as elevenostat, FT895, and SIS17, might represent promising future treatments that target lipid metabolic dysregulation in cancers. SIRT3 has a role in mitochondrial fatty-acid β-oxidation by regulating long-chain acyl-CoA dehydrogenase (LCAD). SIRT6 is indispensable for hepatic β-oxidation by deacetylating the peroxisome proliferator-activated receptor α (PPARα) coactivator nuclear receptor coactivator 2 (NCOA2) at K780. Following palmitic acid treatment, SIRT6 interacts with p53 to regulate de novo cardiolipin biosynthesis and maintain lipid homeostasis.

Amino acids are also involved in tumorigenesis. SIRT3 depletion suppresses glutamate dehydrogenase (GDH/GLUD), which impairs glutamine flux to the TCA cycle and causes reduction of acetyl-CoA pools. SIRT4 is a lipoamidase that diminishes the activity of the pyruvate dehydrogenase complex (PDH) by hydrolyzing the lipoamide cofactor dihydrolipoyllysine acetyltransferase (DLAT). Furthermore, SIRT4 represses GDH activity through its ADP-ribosyltransferase function. SIRT4 deficiency activates GDH, stimulating amino acid-mediated insulin secretion in insulinoma cells. SIRT4 also mediates other PTMs, including methylglutarylation, hydroxymethylglutarylation and 3-methylglutaconylation, and intermediates of these PTMs contribute to leucine oxidation. Indeed, SIRT4-KO induces leucine disordered metabolism and leads to glucose intolerance and insulin resistance. Meanwhile, elevated SIRT5 expression in breast cancer mediates glutaminase desuccinylation and protects glutaminase from ubiquitin-mediated degradation; this effect has been associated with a poor prognosis in breast cancers. SIRT3 and SIRT5 also mediate desuccinylation and deacetylation of SHMT2, respectively, suggesting that suppression of serine catabolism might represent a novel strategy to restrain tumor growth.

Hypoxia and Angiogenesis

Activated HIFs (HIF-1α, HIF-2α, HIF-3α, and HIF-1β) have vital roles in adaptive responses, with HIF-1α and HIF-2α in particular being associated with tumorigenesis and angiogenesis in response to hypoxia. Notably, SAHA specifically induces the accumulation of HIF-2α rather than HIF-1α in soft tissue sarcomas. HIF-1α is ubiquitinated by von Hippel-Lindau (VHL) or by binding to p53-MDM2, inducing proteasomal dependent degradation. HDAC1 downregulates p53 and VHL expression, and stimulates HIF-1α-dependent angiogenesis. TSA inhibits this process by blocking HIF-1α and the vascular endothelial growth factor (VEGF) receptor. Besides, HDAC4 and HDAC6 directly bind to HIF-1α. HDACi LAQ824, valproic acid (VPA) and trapoxin induce dose-dependent HIF-1α depletion in an VHL-independent manner. The class IIa-selective HDACi TMP195 effectively establishes an anti-tumor microenvironment and induces normalization of tumor vasculature in breast cancers by eliciting recruitment and differentiation of macrophages. TMP195 in combination with chemotherapeutic regimens such as carboplatin or paclitaxel can significantly reduce breast cancer burden.

As for SIRTs, they continuously perform an inhibitory role to HIF-1α-relevant transcriptional and metabolic regulation. During hypoxia, SIRT1 activity is inhibited due to reduced NAD+ levels, which leads to the acetylation and activation of HIF-1α and HIF-2α. SIRT1 negatively regulates angiogenesis by deacetylating FoxO1. In human breast cancers, a SIRT3 deficiency can stabilize HIF-1α. Both SIRT6 and SIRT7 can negatively modulate the expression and activity of HIF-1α and HIF-2α.

Redox and Oxidative Stress

Histone deacetylase inhibitors treatment is often accompanied by oxidative stress related DNA damage that is primarily caused by the generation of reactive oxygen species (ROS). In mammalian cells, two redox systems respond to oxidative stress: the thioredoxin (Trx) system and the glutathione-glutaredoxin (Grx) system. In response to nitric oxide (NO), HDAC2 is S-nitrosylated at Cys 262 and Cys 274, which induces chromatin remodeling to promote gene expression. A pair of redox-sensitive cysteine residues (Cys-667/Cys-669) in HDAC4 are involved in oxidative stress via the formation of intramolecular disulfide bonds. Compared with normal cells, tumor cells are enriched with the antioxidant Trx reductase (TrxR), which might represent a novel therapeutic target. Depsipeptide causes robust DNA damage and apoptosis by inducing ROS generation, primarily through the suppression of TrxR. HDAC5 represses mitochondrial ROS generation, and depletion of HDAC5 provokes nuclear factor, erythroid 2 like 2 (NRF2)-associated transcription. The DNA and RNA binding protein Y-box binding protein 1 (YB-1) binds to NRF2 in response to oxidative stress. Entinostat induces YB-1 acetylation and blocks its binding to NRF2, reducing NRF2 synthesis and increasing ROS levels in sarcoma cells.

Sirtuins primarily serve as antioxidants in redox signaling. SIRT1, -2, and -3 all prevent oxidative stress by inducing or modulating manganese superoxide dismutase (MnSOD). Glucose-6-phosphate dehydrogenase (G6PD) is key enzyme of the pentose phosphate pathway (PPP) that regulates nicotinamide adenine dinucleotide phosphate (NADP)/NADPH levels. NADPH maintains glutathione (GSH) at a reduced state, which serves as an antagonist to prevent ROS generation. In response to oxidative stress, SIRT2 and SIRT3 promote NADPH generation by deacetylating and activating G6PD and IDH2 in the PPP or in the TCA cycle, respectively. The PPP also produces ribose-5-P, which synthesizes nucleotides and generates NAD+, which in turn supports SIRTs activity. SIRT3 also activates NADH quinone oxidoreductase (Complex I) and succinate dehydrogenas (Complex II) in the electron transport chain. Furthermore, in the mitochondrial inter-membrane space, SIRT5 deacetylates cytochrome c. SIRT5 is also present in peroxisomes, where it desuccinylates and inhibits peroxisomal acyl-CoA oxidase 1 (ACOX1). A SIRT5 deficiency in hepatocellular carcinoma (HCC) increases oxidative DNA damage by elevating ACOX1-mediated H2O2 production. By contrast, SIRTs also inhibit antioxidation; for example, SIRT2 deacetylates and suppresses peroxiredoxin (an antioxidant) in breast cancer cells (; Figure 3).

DNA Damage Response

The DDR is a vitally important regulatory mechanism that protects genomic DNA from damage induced by various stimuli. Different levels of DNA damage are inevitably caused by UV radiation and DNA adducts, which are produced by ROS and reactive nitrogen species (RNS), as well as exposure to chemical agents. DNA double-strand breaks (DSBs) are the most severe form of DNA damage and are repaired via one of two pathways: homologous recombination (HR) or non-homologous end-joining (NHEJ). Deacetylation of H3K56 and H4K16 by HDAC1/2 are involved in mediating dynamic chromatin regulation in response to NHEJ. Although H4K16 acetylation attenuates binding of p53 binding protein 1 (53BP1) to H4K20me2, euchromatic histone lysine methyltransferase 1 (EHMT1, also called GLP or KMT1D)-catalyzed H4K16 monomethylation could significantly enhance this binding. Meanwhile, SIRT1 redistributes to DSB foci to promote HR during oxidative stress. NuRD complex subunit, chromodomain-helicase-DNA-binding protein (CHD4), was recently discovered to be recruited by SIRT6 to replace heterochromatin 1 (HP1) at H3K9me3 to ultimately promote chromatin relaxation through HR. SIRT6 also mono-ADP-ribosylates and displaces KDM2A (also called JmjC domain-containing histone demethylase 1A, JHDM1A) from chromatin, which leads to HP1α-dependent H3K9me3 deposition at DSBs and transient transcriptional repression, accompanying with the recruitment of NHEJ factors.

The DDR is controlled by three related kinases: ataxia telangiectasia mutated (ATM), ataxia telangiectasia mutated and Rad3 related (ATR), and DNA-dependent protein kinase catalytic subunits (DNA-PKcs). Once a DSB occurs, the MRE11-RAD50-NBS1 (MRN) complex and the Ku family are rapidly recruited to DSB sites. As the sensor, ATM is recruited to DSB sites by the MRN complex. The interplay between HDAC1 and ATM increases chromatin condensation to prevent radio-sensitivity in response to ionizing radiation. SIRT1 binds to deleted in breast cancer 1 (DBC1), which induces p53 activation. ATM also mediates DBC1 phosphorylation at threonine (Thr) 454 which contributes to DBC1-SIRT1 interactions during DNA damage. Moreover, SIRT1 deacetylates and maintains the hypoacetylation of Nijmegen breakage syndrome protein 1 (NBS1), which is necessary for the ionizing radiation-induced phosphorylation of NBS1 and subsequent MRN complex recruitment to DSB sites. SIRT7 directly binds and deacetylates ATM, which is prerequisite for ATM dephosphorylation and inactivation in the final stage of DNA repair. Panobinostat-induced downregulation of meiotic recombination 11 homolog (MRE11) enhances radio-sensitization of bladder cancer cells by promoting MRE11 ubiquitination that relies on the upregulated E3 inhibitor of apoptosis protein 2 (cIAP2).

ATR and its downstream kinase CHK1 are also involved in the response to DNA replication stress. SAHA slows down replication forks by restricting the ATR pathway. Following the conserved mechanism in yeast, VPA disrupts the formation of single-strand-DNA-RFA nucleofilaments and the activation of the Mec1 (ATR in human) and Rad53 (CHK2 in human) by suppressing the recruitment of replication factor A protein 1 [RFA1, replication protein A (RPA) in human] and DNA damage checkpoint protein Ddc2/LCD1 [ATR interacting protein (ATRIP) in human] to DNA damage sites. Entinostat represses checkpoint signaling during replication stress. Mechanically, HDAC1/2 suppress the cell cycle kinases WEE1 and CDK1 and induce the dephosphorylation of ATM and CHK2 by suppressing the expression of PP2A subunit. Entinostat also induces the incorrect incorporation of NTPs and metabolites during the induction of checkpoint kinase inactivation, which can result in mitosis catastrophe. Therefore, CHK inhibitors might be designed to prevent this event from occurring. Indeed, CHK1 inhibitor treatment combined with HDACi induces cell death via extensive mitotic disruption in a range of solid tumors.

DNA-PKcs is another sensor that is recruited to DSBs by Ku-bound DSB ends. Under conditions of fasting-induced oxidative stress, SIRTs act as protective factors in the DDR. Specifically, SIRT1 deacetylates Ku70, resulting in Ku70-Bcl-2 associated protein X (BAX) disassociation and the transport of BAX away from the mitochondria, leading to stress-induced resistance to apoptosis. SIRT3 also physically interacts with and deacetylates Ku70 to impede BAX translocation to the mitochondria.

SIRTs are highly important for DNA damage repair and genome stability. Recent data have shown that SIRT6 is a novel sensor for initiating the DDR. Deacetylated SIRT6 at K33 by SIRT1 results in SIRT6 polymerization and deposition at γH2AX foci. Moreover, a SIRT6 K33R hypoacetylation mimic can rescue DNA repair defects in SIRT1-deficient cancer cells. SIRT7 is also associated with NHEJ, as a Sirt7 deficiency impairs the recruitment of 53BP1 to DSB sites and inhibits NHEJ efficiency. SIRT7 also deacetylates ATM to mediate ATM inactivation in the final stage of DNA damage repair. SIRT7 acts as a deglutarylase to regulate H4K91 glutarylation (H4K91glu). This process is closely associated with chromatin remodeling in response to DNA damage. Treatment with 5-Fluorouracil (5-FU) induces SIRT7 degradation in the Tat-binding protein 1 (TBP1)-mediated proteasome-dependent pathway, increasing cell radiosensitivity in combination therapy.

Poly ADP-ribose polymerases (PARPs) are central to the activation of several downstream repair mechanisms, including single-strand DNA breaks (SSBs), base-excision repair (BER), HR and NHEJ. SIRTs and PARPs all require NAD+ to elicit function. However, PARP1 consumes NAD+, and this affects NAD+-dependent SIRT activity. Thus, depleting PARP1 increases the catalytic function of SIRTs. Under conditions of oxidative stress, SIRT6 physically binds to and mono-ADP-ribosylates PARP1 at K521 to facilitate DNA repair. SIRT7 is recruited to DSB sites in a PARP1-dependent manner, and catalyzes H3K122 desuccinylation, which facilitates chromatin compaction and DNA repair. Based on synthetic lethality, PARP inhibitors induce genomic instability in breast cancer susceptibility protein (BRCA1/2)-deficient cancer cells. The combined use of HDAC and PARP inhibitors will likely be of great benefit for patients with BRCA1/2-deficient malignancies.

With the exception of DSBs, cancer cells can overcome DNA damage-induced cytotoxicity through BER, nucleotide excision repair (NER) and mismatch repair. Uracil-DNA N-glycosylase isoform 2 (UNG2) has a role in BER and can be deacetylated at K78 by HDAC, boosting disassociation from its E3 ubiquitin-like containing PHD and ring finger domain 1 (UHRF1) when stimulated by ROS. HDACi combined with genotoxic agents results in UNG2 degradation, resulting in a robust cell death effect. SIRT1 interacts with xeroderma pigmentosum group A (XPA) in NER by directly deacetylating XPA or mediating XPA binding to ATR to prevent UV irradiation. HDAC10 is mainly involved in DNA mismatch repair by deacetylating mutS homolog 2 (MSH2) at K73.

Besides, a number of other histone modifications are also actively involved in these DNA repair pathways, but are beyond the scope of this review. Suffice to say that the multiple sites of H3 and H4 acetylation are not absolutely related to checkpoint activation because the conversion of lysine to other amino acids can still activate checkpoints.

Cell Cycle

Cell cycle dysregulation is a central hallmark of oncogenesis; as such, cell cycle regulators are considered promising targets for cancer treatment. HDACs are often involved in cell cycle checkpoints. HDAC3-mediated deacetylation of cyclin A affects the progression of the S phase and G2/M transitions. HDAC10 depletion induces G2-M transition arrest through the regulation of cyclin A2. Mechanically, HDAC10 depletion induces the downregulation of high mobility group AT hook 2 (HMGA2), which leads to enrichment of E4F transcription factor 1 (a cyclin A2 repressor) at the cyclin A2 promoter and G2-M arrest. Regarding combination therapies, the CDK9 inhibitor dinaciclib and panobinostat together induce apoptosis over the short-term in MLL-AF9-driven acute myeloid leukemia (AML). The emerging hybrid inhibitor Roxyl-zhc-84, which concordantly inhibits HDACs and CDKs, induces G1-phase arrest and apoptosis in ovarian and breast cancer cells.

Spindle assembly checkpoint (SAC) is involved in regulating mitosis. Budding uninhibited by benzymidazol related-1 (BubR1), a component of the SAC, must be deacetylated by HDAC2/3 to initiate mitotic exit. HDAC3 induces SAC activation and the dissociation of sister chromatids. SIRT2 is strongly associated with mitosis exit. SIRT2 regulates the anaphase-promoting complex/cyclosome (APC/C) by deacetylating its cofactors, cell-division cycle protein 20 (CDC20) and CDC20 homolog 1 (CDH1), which are both required for mitosis exit and chromosome segregation. SIRT2 also deacetylates α-tubulin at K40 to promote cell mobility. The SIRT2 inhibitor SirReal2 induces tubulin hyperacetylation and BubR1 destabilization. HDAC5 induces the transcription of the mitosis kinase Aurora A, by repressing the expression of the E3 ligase NEDD4. Combination of the Aurora A kinase inhibitor alisertib with romidepsin causes dose-dependent cytotoxicity of lymphoma cells.

p21Cip/Waf1 is a cyclin-dependent kinase inhibitor (CKI). HDACi induces p21 expression by re-activating hyperacetylation of H3 and H4 in its promoter region. Furthermore, depsipeptide induces p53 phosphorylation at Thr 18, which is a requirement for subsequent p53 acetylation at K373/382 and p21 activation. In liver cancer, the HDAC8-selective inhibitor PCI-34051 can induce p21 expression and G2-M phase cell cycle arrest. Nevertheless, p21 and p16 are activated by HDACi in a p53-independent manner. Namely, SIRT7 indirectly modulates p21-mediated cell cycle arrest by elevating p53 activity. SIRT7 physically binds and deacetylates P300/CBP-associated factor (PCAF) at K720, and this interaction is enhanced under conditions of glucose deprivation. As a result, PCAF binding to MDM2 is promoted, resulting in a triggering of MDM2 degradation via the ubiquitin-dependent proteasome pathway. Finally, in p21-KO lymphomas, p27Kip1 (CDKN1B) functions in a p21-independent manner to induce cell cycle arrest after SAHA treatment.

Apoptosis

Apoptosis is a physiologically programmed cell death pathway that is essential for the maintenance of organismal homeostasis. Apoptosis is controlled by the B-cell lymphoma 2 (Bcl-2) family of proteins, which includes both pro-survival and pro-apoptotic proteins that control cell fate.

Regarding the intrinsic apoptotic pathway, the Bcl-2 interacting mediator of cell death (Bim), a Bcl-2 homology 3 (BH3)-only proapoptotic protein, is upregulated by depsipeptide via FoxO1 acetylation. Panobinostat elevates Sry-box transcription factor 7 (SOX7) expression and suppresses lung cancer cell proliferation. Mechanically, SOX7 triggers apoptosis by preventing Bim from proteasome-mediated degradation. The N-terminal truncated form of p63, ΔNp63, belongs to the p53 family, but acts as an oncoprotein. In squamous cell carcinoma, HDAC1 and HDAC2 form a complex with ΔNp63 to suppress the proapoptotic gene expression such as p53 upregulated modulator of apoptosis (PUMA).

Histone deacetylase inhibitors treatment also affects the anti-apoptotic members of the Bcl-2 family. Specifically, depsipeptide induces apoptosis by decreasing the expression of pro-survival factors Bcl-2 and B-cell lymphoma-extra-large (Bcl-xL). The HDAC6-selective inhibitor ricolinostat exerts pronounced anti-lymphoma effects both alone and in combination with the alkylating agent bendamustine, by impairing the activation of caspase 8, -9, -3, and the Bcl-2 family. Myeloid cell leukaemia 1 (Mcl-1) is an E3-bound, anti-apoptotic protein that is involved in mitotic arrest. HDACi-induced Mcl-1 phosphorylation likely promotes apoptosis, whereas mutant phosphorylated Mcl-1 resists HDACi by binding to BH3-only proapoptotic proteins.

p53 is a crucial activator of apoptosis. HDAC1-3 all downregulate p53 activity, which represses p53-mediated activation of the pro-apoptotic gene BAX. Acetylation of p53 at K120 upregulates apoptotic peptidase activating factor 1 (Apaf-1) in the mitochondria. Under genotoxic stress, HDAC5 deacetylates p53 at K120, which activates pro-apoptotic target genes. Furthermore, HDAC6 directly deacetylates p53 at K120, which is required for p53-induced apoptosis in tumors with AT-rich interaction domain 1A (ARID1A) mutations.

In summary, HDACi promote apoptosis via the intrinsic mitochondrial pathway, decreasing the expression of key anti-apoptotic factors (eg. Mcl-1, Bcl-2, and Bcl-xL), and/or increasing the expression of pro-apoptotic proteins (eg. BAX, Bim, Noxa and PUMA). HDACi also facilitate the activation of extrinsic apoptotic pathways, such as TRAIL, driving mitochondrial outer membrane polarization (MOMP) and ultimately caspase-mediated cell death.

Degradation System

The modulation of protein degradation is of critical importance for cell function. Protein degradation occurs via two major pathways: the ubiquitin-dependent proteasome pathway and autophagy system.

Autophagy

Autophagy is a degradation process whereby autophagosomes engulf and recycle nutrient sources in response to energetic demands and organelle turnover. Autophagy can be effectively promoted by HDACs. For example, depletion of HDAC10 perturbs autophagy flux through increased LC3-II/I, and the accumulation of p62 and acidic vesicular organelles. HDAC10 inhibition results in increased sensitivity to cytotoxic reagents. Sirt1 also forms complexes with autophagy related protein 5 (ATG5), ATG7 and ATG8 to promote autophagy, with organelles in Sirt1–/– mice being markedly damaged. The SIRT1 and -2 inhibitor tenovin-6 activates p53 and seems to be a specific regulator of mitochondrial acetylation. Tenovin-6 suppresses Ewing sarcoma cells by regulating the NOTCH signaling pathway, and perturbs autophagic flux in chronic lymphocytic leukemia (CLL) cells and pediatric soft tissue sarcoma cells. However, HDACs also interrupt autophagy, and various HDACi induce cancer cell death by promoting autophagy. In HDAC10-KO HeLa cells, chaperone-mediated autophagy (CMA) instead of macroautophagy is activated by the accumulation of lysosome-associated protein type 2A (LAMP2A)-positive lysosomes and the degradation of CMA substrate glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In response to serum starvation or oxidative stress, SIRT2 inhibition induces acetylated FoxO1 to locate in the cytoplasm, accelerating autophagy through interaction with ATG7. Under nutrient-rich conditions, FoxK1/2 bind to HDAC complex and restricts autophagic flux through the transcriptional repression of autophagy gene. Under condition of nutrient deprivation, inhibition of the AKT serine/threonine kinase pathway facilitates nuclear import of FoxO3, which competitively replaces FoxK to bind the autophagy-associated gene promoters and upregulation of autophagy. Moreover, VPA activates autophagy by blocking HDAC1-mediated regulation of AKT pathway. The nutrient-sensor mammalian target of rapamycin (mTOR) negatively modulates downstream Unc-51-like autophagy activating kinase 1 (ULK1) that is involved in the non-transcriptional autophagic pathway. SAHA induces mTOR suppression, which ultimately activates autophagy by upregulating ULK1. Of note, SAHA-induced autophagy seems to serve as a pro-survival mechanism to ameliorate SAHA-induced apoptosis by downregulating apoptotic factors. VPA also induces Sae2 [C-terminal-binding protein interacting protein (CtIP) in human] degradation in an autophagy related manner to impair HR-mediated DNA repair. As such, it seems that autophagy performs a dual role in DNA damage repair, depending on the cell states or DNA damage degree.

Proteasome-Dependent Degradation

In addition to autophagy, proteasome-dependent degradation is also critical for cell function. HDACs target various E3s to affect basal cellular function. For example, panobinostat upregulates the E3 cIAP2 that causes the ubiquitination and proteasomal degradation of MRE11, elevating cellular sensitivity to chemoradiation. HDAC6 also modulates aggresome formation and the clearance of polyubiquitinated and misfolded proteins. In terms of therapeutic development, suppressing the aggresome pathway results in the accumulation of misfolded proteins, causing autophagy-associated DNA damage and apoptosis of cancer cells. Proteasome inhibitors (PIs), such as the United States Food and Drug Administration (FDA)-approved bortezomib (BTZ), have similar roles in preventing the degradation of polyubiquitin-misfolded proteins, which increases the production of ROS and disturbs DNA repair in tumor cells. However, long-term treatment with BTZ leads to drug-resistance in most patients. Low concentrations of HDACi combined with BTZ can downregulate anti-apoptotic proteins and upregulate pro-apoptotic proteins, thus accelerating cell death. Combining the HDAC6-selective inhibitor tubacin with BTZ induces significant anti-tumor activity triggering c-Jun NH2-terminal kinase (JNK)-caspase signaling and endoplasmic reticulum (ER) stress. Another HDAC6 inhibitor, WT161, promotes the accumulation of acetylated tubulin and overcomes BTZ resistance to promote multiple myeloma (MM) cell death. RTS-V5, a dual inhibitor that targets HDAC6 and the 20S subunit of the proteasome, also possesses potent and selective anti-tumor activity in leukemia and MM cell lines.

Epithelial-Mesenchymal Transition, Cancer Stem Cells, and Senescence

Epithelial-mesenchymal transition (EMT) is characterized by the loss of the tight intercellular connections normally found in epithelial cells that then undergo cytoskeleton rearrangement and adopt the mesenchymal cell phenotype, which is associated with migration. Notably, cancer cell migration and invasion are promoted by a series of EMT-associated factors (such as SNAIL, ZEB, SLUG and TWIST). These factors induce EMT-related stem cell properties and promote tumorigenesis via PTMs. S-nitrosylation of HDAC2 is regulated by endothelial nitric oxide synthase (eNOS) that is a crucial enzyme for NO synthesis, allowing ZEB1 re-activation. During hypoxia, HDAC3 is essential for the activation of mesenchymal gene expression by the interaction with WD repeat domain 5 (WDR5). The transforming growth factor-β (TGF-β)-SMAD signaling pathway is the most important EMT stimulation pathway. HDAC6 also has an essential role in EMT by activating SMAD3. SMAD3 and -4 induce SIRT7 transcriptional repression by forming a complex with HDAC8. HDAC8 inhibition significantly suppresses TGF-β signaling via SMAD-SIRT7 axis, and as a consequence, attenuates lung metastases of breast cancer. Class I HDACi 4SC-202 notably attenuates TGF-β-induced EMT. By contrast, HDAC10 exhibits a potential TSG role by downregulating Sry-box transcription factor 9 (SOX9) in KRAS-driven lung adenocarcinoma. Furthermore, HDAC10 deficiency results in TGF-β pathway activation, leading to the induction of SOX9 and KRAS-expressing stem-like tumor growth. Cancer-associated fibroblasts (CAFs) secrete extracellular matrix (ECM) that assists tumor progression and invasion. Scriptaid, a selective inhibitor of HDAC1, −3, and −8, represses TGF-β-mediated CAF by inhibiting ECM secretion and cell invasion. Of note, E-cadherin inhibits EMT, thus reduced E-cadherin expression indicates that “stemness” is increasing in cancer cells. HDAC and the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) dual inhibitor JMF3086 restores E-cadherin expression and attenuates vimentin expression and stemness in NSCLC, which recovers sensitivity to gefitinib which is an epidermal growth factor receptor (EFGR) tyrosine kinase inhibitor (TKI).

Cancer stem cells are hard to eradicate and prone to drug-resistance. HDAC3 interacts with p53 and forms complexes with tumor antigens melanoma antigen family A2 (MAGE-A2), establishing the resistance of melanoma cells to chemotherapeutic agents. In refractory and recurrent leukemia, HDAC8-selective inhibitor significantly restores acetylation and p53 activity, inducing apoptosis of AML cells but not of normal hematopoietic stem cells. In addition, SIRT1 inhibition increases the efficiency of BCR-ABL TKI imatinib mesylate to eliminate quiescent leukemia stem cells by reactivating p53.

Sirtuins are also closely involved in aging-related oncogene expression. Both SIRT6 and SIRT7 modulate long interspersed elements-1 (LINE-1, L1) expression and retrotransposition. SIRT6 mono-ADP-ribosylates the Krüppel-associated box domain-associated protein 1 (KAP1/TRIM28) and facilitates the KAP1 interaction with HP1α, resulting in the packaging of L1 elements into heterochromatin. SIRT7 directly binds L1 elements and promotes L1 sequences association with the nuclear lamina protein (Lamin A/C) by deacetylating H3K18. These repressive functions of L1 highlight the protective roles of SIRTs on genome stability through preventing retrotransposition events. SIRT6 and SIRT7 deficiency result in aberrant heterochromatin and L1 activation especially in age-related diseases. Nucleoside reverse-transcriptase inhibitors can reverse a SIRT6 and SIRT7 deficiency by upregulating different immune signalings, such as the type I IFN pathway and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, respectively (;; Figure 4).

HDAC Inhibitors in Cancer Therapy

In the 1970s, sodium butyrate was discovered to transform red leukemia cells into normal cells, and to resynthesize hemoglobin. This process was accompanied by strong histone hyperacetylation, and resulted in the discovery of the first HDACi. In isolated the first natural HDACi, TSA, which was derived from Streptomyces hygroscopicus. Following the discovery of TSA, trapoxin was isolated from fungi and also found to act as an HDACi. A number of natural inhibitors have since been extracted from fungi, marine life, and plants that contain sulfur, polyphenol, flavonoid, terpenoid, selenium, and other organic molecules. At present, HDACi are mainly divided into four categories following the FDA approval: (i) hydroxamic acids or hydroxamates, such as SAHA, panobinostat and belinostat; (ii) cyclic peptides, including depsipeptide; (iii) benzamides, such as chidamide; and (iv) short-chain fatty acids, including VPA (;;; Table 3).

Efficiency of HDACi

From preclinical studies to clinical trials, HDACi have demonstrated powerful therapeutic effects in various cancers. HDACi can significantly attenuate tumor burden by limiting tumor growth and restraining aberrantly proliferated vessels. HDACi can also induce DNA damage, cell cycle arrest, apoptosis and autophagy to promote cancer cell death mentioned above. Some novel SIRT inhibitors, such as MC2494, MHY2245, MHY2256, tenovin-6, and YC8-02, also perform diverse anti-tumor activities through mediating apoptosis or autophagy.

Activation of the immune response by HDACi could also be an effective innate method to prevent cancer relapse when administered in a regimen with immunotherapeutic. The class IIa HDACi TMP195 efficiently improves the durability of tumor reduction in breast cancer by strengthening the phagocytic role of macrophages that are involved in the IFNγ axis; it also activates the adaptive anti-tumor immune response. Upon immune checkpoint blockade, TMP195 combined with an anti-programmed cell death-1 (PD-1) regimen could significantly reduce the tumor volume and induce a durable response in breast cancer. Myeloid-derived suppressor cells (MDSCs) suppress T-cell functions and promote tumor metastasis via the formation of an immunosuppressive tumor microenvironment. Entinostat exhibits remarkable curative effects when combined with PD-1 and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockade; it has been shown to significantly reduce the number of MDSCs. 5-azacytidine combined with entinostat can also suppress MDSCs by downregulating C-C chemokine receptor type 2 (CCR2) and C-X-C chemokine receptor type 2 (CXCR2) expressions that ultimately, stimulates MDSC differentiation into a macrophage-like phenotype. In human epidermal growth-factor receptor 2-positive (HER2+) breast cancer, panobinostat combined with trastuzumab (anti-HER2) stimulates the release of CXCR3-reactive chemokines and enhances the recruitment of tumor-associated natural killer (NK) cells to achieve eradication of tumors.

The first FDA-approved HDAC inhibitor, SAHA, belongs to the hydroxamic acid class, approved to treat patients with cutaneous T cell lymphoma (CTCL). In many clinical trials, SAHA has proven effective against advanced and refractory tumors, alone or in combination with other inhibitors. Subsequently, the cyclic peptide romidepsin was approved by the FDA in 2009 to treat CTCL. Panobinostat and belinostat were both approved by the FDA in 2014 to treat peripheral T cell lymphoma (PTCL), with belinostat gaining additional approval from the European Medicines Agency (EMA). Both panobinostat and belinostat are classified as hydroxamic acids. Meanwhile, chidamide has become the first benzamide HDACi to be approved by the China Food and Drug Administration(CFDA) in 2015, for the treatment of relapsed and refractory PTCL1,2,3,4. Most SIRT inhibitors still remain in the preclinical stages. So far, only nicotinamide (vitamin B3) has been used to treat cancer in clinical trials (e.g., NCT02416739 and NCT00033436). Nicotinamide has shown a potential role in inhibiting non-melanoma skin cancers that are principally generated by UV. Compared to other HDACi, nicotinamide exhibits the most catalytic sites: it is predominantly sensitive to acetylation sites in nuclear proteins that are involved in diverse biological processes.

Application of Selective Inhibitors and Combination Therapy

With the development of HDACi, numerous clinical trials are ongoing or completed currently for cancer therapy. Many HDACi have already been approved for hematological malignancies and lymphomas, while clinical studies are ongoing for refractory, advanced and recurrent solid tumors (Table 4). For instance, the use of the HDAC6-selective inhibitor ACY1215 (also named rocilinostat or ricolinostat) as a regimen for relapsed or refractory lymphoma and MM is currently in phase I/II clinical trials [Lymphoma (NCT02091063), MM (NCT01323751, NCT01583283, NCT01997840)]. HDACi with multiple targets have also been developed and tested in clinical trials, such as the dual HDAC and phosphoinositide-3 kinase (PI3K) inhibitor CUDC-907 (also called fimepinostat), which has been reported to inhibit Myc transcriptional expression and reduce Myc-mediated proliferation of multiple cancer cell lines. The safety, tolerability and efficacy of CUDC-907 has been assessed in phase I/II trials. CUDC-101 is another multiple-target inhibitor that blocks HDACs, the epidermal growth factor receptor (EGFR) and HER2 in head and neck squamous cell cancer.

Combination drugs can inhibit tumorigenesis from different aspects. A clinical phase I trial of SAHA combined with the autophagy inhibitor MLN9708 shows potential for this regimen in advanced p53-mutant malignancies (NCT02042989). Hydroxychloroquine (HCQ) is a common autophagy-targeting reagent that has been used in clinical research. Several phase I/II clinical studies (e.g., NCT02316340 and NCT01023737) have thus tested the safety, tolerability and pharmacological efficacy of SAHA combined with HCQ in solid tumors. A phase I/II trial targeting BTZ-resistant MM cancer has found that a synergistic regimen of using ricolinostat and dexamethasone could be safe and well-tolerated in affected patients. A recent phase III clinical trial found that a combination of chidamide and exemestane has therapeutic potential for postmenopausal patients with advanced, hormone receptor-positive (HR+), HER2– breast cancer and who have failed to respond to endocrine therapy. Combining the SIRT1 inhibitor Ex527 with the WEE1 inhibitor MK-1775 produces efficient effects in lung cancers by impairing HR repair and mitotic catastrophe-associated apoptosis.

The overall survival (OS) and progression-free survival (PFS) are common and quite important indicators in the clinical trials. A phase I/II clinical study targets patients with metastatic clear cell renal cell carcinoma (ccRCC) by treatment with entinostat and high-dose interleukin-2 (IL2) that downregulates forkhead box P3 (Foxp3) expression and function of regulatory T cells (Treg). The median PFS reaches 13.8 months, and the median OS is 65.3 months [NCT01038778]. A phase III trial enrolled 768 patients with relapsed MM exhibits that panobinostat shows the median OS of panobinostat (40.3 months) versus that of placebo (35.8 months) based on the existing treatments of bortezomib and dexamethasone. And patients who had received previous regimens such as immunomodulatory drug and bortezomib, median OS was only 25.5 months when received panobinostat, bortezomib, and dexamethasone versus that was merely 19.5 months who received placebo [NCT01023308]. These HDACi significantly exhibit potential median OS and PFS for patients with advanced tumors.

Limitations of HDACi

However, in a randomized, double-blind and placebo-controlled phase III trial, vorinostat did not improve OS and could not be recommended as a therapy as a second-line or third-line drug for patients with advanced malignant pleural mesothelioma. Moreover, a phase III study that recruited 370 patients with Sézary syndrome or relapsed or refractory mycosis fungoides in CTCL from different countries of the world showed that the overall response rate to vorinostat was less efficient than that to mogamulizumab, a novel monoclonal antibody against CCR4 that significantly prolongs PFS. The overall response to vorinostat in this study was significantly lower than reported in a previous study. Besides, in a phase II trial, mocetinostat did not reverse chemoresistance in patients with previous gemcitabine-resistant leiomyosarcoma and could not significantly prolong the median PFS of patients.

Sirtuins constitute a relatively unique class of HDACs; as such, SIRT modulators are attracting great interest in the research community. A novel SIRT7 inhibitor has been identified to inhibit tumor growth by blockade of the direct interaction of SIRT7 and p53. However, there are also several reports demonstrating an indirect interaction between SIRT7 and p53. Thus, it is urgent to develop specific SIRT inhibitors for cancer therapy according to reasonable mechanisms. It is worth noting that SIRT activators and sirtuin-activating compounds (STACs) have been developed and studied in clinical trials to investigate their anti-aging, anti-inflammatory and metabolic regulatory effects. Nevertheless, the SIRT1 activator SRT2183 has also been shown to inhibit growth and to promote cell death by causing ER stress in glioma cells.

Besides, most of clinical trials of HDACi have reported many adverse effects, including bleeding caused by different grades of thrombocytopenia, susceptibility to infection caused by neutropenia, anemia caused by hemoglobin reduction, arrhythmia, myocardial hypertrophy, neurotoxicity, and gastrointestinal toxicity such as nausea, vomiting, fatigue, diarrhea as well as electrolyte disturbance such as hypophosphatemia and hyponatremia. The most adverse effect reported is cell death caused by continuous cytotoxicity, as these agents also kill immortalized and normal cells from different tissues.

Discussion and Perspectives

To date, only five HDACi have been approved by health authorities globally. Numerous clinical trials are currently evaluating the safety, application, and therapeutic benefits of HDAC inhibition when treating cancers, neurological disorders and other human diseases. Thus far, it is clear that FDA-approved HDACi have both beneficial and adverse effects. These effects might be accompanied by genomic instability, abnormal gene transcription, interference with chaperone protein function and free radical generation, which currently limit the therapeutic potential of HDACi.

Analyses of HDAC structural conformations and molecular mechanisms are necessary to improve treatment development. Complicating the application of HDACi is that the modification of the substrates by HDAC has spatio-temporal and tissue specificity. Consequently, dose-dependent and time-dependent treatments have different effects on gene expression regulation, various protein PTMs and chromatin remodeling. For now, combining different drugs to inhibit pathways such as tumor proliferation or angiogenesis, or to stimulate apoptosis requires more consideration.

Isolating the anti-cancer effects of HDACi and then synthesizing molecules with highly specific targets could be a promising avenue for cancer treatment in the future. Further investigation into combination treatments involving oncoprotein inhibitors and specific HDACi is also warranted. Overall, it seems that combination therapies have the advantage of reducing drug toxicity and lowering dose demand. SIRT protective factors should also be considered. Pending additional work to clarify HDACi that target specific HDACs or can be combined with other treatments, such as DNA methylation inhibitors or autophagy inhibitors, could be of great benefit to patients with cancers that have failed to respond to conventional treatments.

Author Contributions

GL wrote the primary manuscript and YT revised the manuscript. W-GZ conceived and designed the manuscript. All authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References 522

  1. 1.

    Adams C. M. Eischen C. M. (2016 ). Histone deacetylase inhibition reveals a tumor-suppressive function of MYC-regulated miRNA in breast and lung carcinoma. Cell Death Differ. 23 1312–1321.

    Not in our library10.1038/cdd.2016.9

  2. 2.

    Adams C. M. Hiebert S. W. Eischen C. M. (2016 ). Myc induces miRNA-mediated apoptosis in response to HDAC inhibition in hematologic malignancies. Cancer Res. 76 736–748.

    Not in our library10.1158/0008-5472.can-15-1751

  3. 3.

    Agarwal N. Mcpherson J. P. Bailey H. Gupta S. Werner T. L. Reddy G. (2016 ). A phase I clinical trial of the effect of belinostat on the pharmacokinetics and pharmacodynamics of warfarin. Cancer Chemother. Pharmacol. 77 299–308.

    Not in our library10.1007/s00280-015-2934-1

  4. 4.

    Ago T. Liu T. Zhai P. Chen W. Li H. Molkentin J. D. (2008 ). A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy. Cell 133 978–993.

    Not in our library10.1016/j.cell.2008.04.041

  5. 5.

    Ahn B. H. Kim H. S. Song S. Lee I. H. Liu J. Vassilopoulos A. (2008 ). A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc. Natl. Acad. Sci. U.S.A. 105 14447–14452.

    Not in our library10.1073/pnas.0803790105

  6. 6.

    Alexandrova E. M. Yallowitz A. R. Li D. Xu S. Schulz R. Proia D. A. (2015 ). Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment. Nature 523 352–356.

    Not in our library10.1038/nature14430

  7. 7.

    Ali I. Ruiz D. G. Ni Z. Johnson J. R. Zhang H. Li P. C. (2019 ). Crosstalk between RNA Pol II C-terminal domain acetylation and phosphorylation via RPRD Proteins. Mol. Cell 74 1164–1174.e4.

    Not in our library10.1016/j.molcel.2019.04.008

  8. 8.

    Allfrey V. G. Faulkner R. Mirsky A. E. (1964 ). Acetylation and methylation of histones and their possible role in the regulation of Rna synthesis. Proc. Natl. Acad. Sci. U.S.A. 51 786–794.

    Not in our library10.1073/pnas.51.5.786

  9. 9.

    Amano H. Chaudhury A. Rodriguez-Aguayo C. Lu L. Akhanov V. Catic A. (2019 ). Telomere dysfunction induces sirtuin repression that drives telomere-dependent disease. Cell Metab. 29 1274–1290.e9.

    Not in our library10.1016/j.cmet.2019.03.001

  10. 10.

    Anastas J. N. Zee B. M. Kalin J. H. Kim M. Guo R. Alexandrescu S. (2019 ). Re-programing Chromatin with a Bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG. Cancer Cell 36 528–544.e10.

    Not in our library10.1016/j.ccell.2019.09.005

  11. 11.

    Anderson K. A. Huynh F. K. Fisher-Wellman K. Stuart J. D. Peterson B. S. Douros J. D. (2017 ). SIRT4 is a lysine deacylase that controls leucine metabolism and insulin secretion. Cell Metab. 25 838–855.e15.

    Not in our library10.1016/j.cmet.2017.03.003

  12. 12.

    Aramsangtienchai P. Spiegelman N. A. He B. Miller S. P. Dai L. Zhao Y. (2016 ). HDAC8 Catalyzes the Hydrolysis of Long Chain Fatty Acyl Lysine. ACS Chem. Biol. 11 2685–2692.

    Not in our library10.1021/acschembio.6b00396

  13. 13.

    Ardestani P. M. Liang F. (2012 ). Sub-cellular localization, expression and functions of Sirt6 during the cell cycle in HeLa cells. Nucleus 3 442–451.

    Not in our library10.4161/nucl.21134

  14. 14.

    Ayer D. E. (1999 ). Histone deacetylases: transcriptional repression with SINers and NuRDs. Trends Cell Biol. 9 193–198.

    Not in our library10.1016/s0962-8924(99)01536-6

  15. 15.

    Azagra A. Roman-Gonzalez L. Collazo O. Rodriguez-Ubreva J. De Yebenes V. G. Barneda-Zahonero B. (2016 ). In vivo conditional deletion of HDAC7 reveals its requirement to establish proper B lymphocyte identity and development. J. Exp. Med. 213 2591–2601.

    Not in our library10.1084/jem.20150821

  16. 16.

    Azzaoui I. Uhel F. Rossille D. Pangault C. Dulong J. Le Priol J. (2016 ). T-cell defect in diffuse large B-cell lymphomas involves expansion of myeloid-derived suppressor cells. Blood 128 1081–1092.

    Not in our library10.1182/blood-2015-08-662783

  17. 17.

    Bagchi R. A. Ferguson B. S. Stratton M. S. Hu T. Cavasin M. A. Sun L. (2018 ). HDAC11 suppresses the thermogenic program of adipose tissue via BRD2. JCI Insight 3:e120159.

    Not in our library10.1172/jci.insight.120159

  18. 18.

    Baker A. Gregory G. P. Verbrugge I. Kats L. Hilton J. J. Vidacs E. (2016 ). The CDK9 inhibitor dinaciclib exerts potent apoptotic and antitumor effects in preclinical models of mll-rearranged acute myeloid leukemia. Cancer Res. 76 1158–1169.

    Not in our library10.1158/0008-5472.can-15-1070

  19. 19.

    Balasubramaniam S. Redon C. E. Peer C. J. Bryla C. Lee M. J. Trepel J. B. (2018 ). Phase I trial of belinostat with cisplatin and etoposide in advanced solid tumors, with a focus on neuroendocrine and small cell cancers of the lung. Anticancer Drugs 29 457–465.

    Not in our library10.1097/cad.0000000000000596

  20. 20.

    Ban J. Aryee D. N. Fourtouna A. Van Der Ent W. Kauer M. Niedan S. (2014 ). Suppression of deacetylase SIRT1 mediates tumor-suppressive NOTCH response and offers a novel treatment option in metastatic Ewing sarcoma. Cancer Res. 74 6578–6588.

    Not in our library10.1158/0008-5472.can-14-1736

  21. 21.

    Bantscheff M. Hopf C. Savitski M. M. Dittmann A. Grandi P. Michon A. M. (2011 ). Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nat. Biotechnol. 29 255–265.

    Not in our library10.1038/nbt.1759

  22. 22.

    Bao J. Lu Z. Joseph J. J. Carabenciov D. Dimond C. C. Pang L. (2010 ). Characterization of the murine SIRT3 mitochondrial localization sequence and comparison of mitochondrial enrichment and deacetylase activity of long and short SIRT3 isoforms. J. Cell. Biochem. 110 238–247.

    Not in our library10.1002/jcb.22531

  23. 23.

    Bao X. Liu Z. Zhang W. Gladysz K. Fung Y. M. E. Tian G. (2019 ). Glutarylation of histone H4 Lysine 91 regulates chromatin dynamics. Mol. Cell 76 660–675.e9.

    Not in our library10.1016/j.molcel.2019.08.018

  24. 24.

    Bao Y. Tong L. Song B. Liu G. Zhu Q. Lu X. (2020 ). UNG2 deacetylation confers cancer cell resistance to hydrogen peroxide-induced cytotoxicity. Free Radic. Biol. Med. 160 403–417.

    Not in our library10.1016/j.freeradbiomed.2020.06.010

  25. 25.

    Barber M. F. Michishita-Kioi E. Xi Y. Tasselli L. Kioi M. Moqtaderi Z. (2012 ). SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 487 114–118.

    Not in our library10.1038/nature11043

  26. 26.

    Barker H. E. Paget J. T. Khan A. A. Harrington K. J. (2015 ). The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat. Rev. Cancer 15 409–425.

    Not in our library10.1038/nrc3958

  27. 27.

    Bertos N. R. Gilquin B. Chan G. K. Yen T. J. Khochbin S. Yang X. J. (2004 ). Role of the tetradecapeptide repeat domain of human histone deacetylase 6 in cytoplasmic retention. J. Biol. Chem. 279 48246–48254.

    Not in our library10.1074/jbc.m408583200

  28. 28.

    Betsch A. Rutgeerts O. Fevery S. Sprangers B. Verhoef G. Dierickx D. (2018 ). Myeloid-derived suppressor cells in lymphoma: the good, the bad and the ugly. Blood Rev. 32 490–498.

    Not in our library10.1016/j.blre.2018.04.006

  29. 29.

    Bhardwaj A. Das S. (2016 ). SIRT6 deacetylates PKM2 to suppress its nuclear localization and oncogenic functions. Proc. Natl. Acad. Sci. U.S.A. 113 E538–E547.

    Not in our library10.1073/pnas.1520045113

  30. 30.

    Bhaskara S. Chyla B. J. Amann J. M. Knutson S. K. Cortez D. Sun Z. W. (2008 ). Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol. Cell 30 61–72.

    Not in our library10.1016/j.molcel.2008.02.030

  31. 31.

    Bhaskara S. Knutson S. K. Jiang G. Chandrasekharan M. B. Wilson A. J. Zheng S. (2010 ). Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 18 436–447.

    Not in our library10.1016/j.ccr.2010.10.022

  32. 32.

    Bhatia S. Krieger V. Groll M. Osko J. D. Ressing N. Ahlert H. (2018 ). Discovery of the first-in-class dual histone deacetylase-proteasome inhibitor. J. Med. Chem. 61 10299–10309.

    Not in our library10.1021/acs.jmedchem.8b01487

  33. 33.
    SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer · 2020
    No notice
  34. 34.

    Bitler B. G. Wu S. Park P. H. Hai Y. Aird K. M. Wang Y. (2017 ). ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat. Cell Biol. 19 962–973.

    Not in our library10.1038/ncb3582

  35. 35.

    Blackford A. N. Jackson S. P. (2017 ). ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol. Cell 66 801–817.

    Not in our library10.1016/j.molcel.2017.05.015

  36. 36.

    Blank M. F. Chen S. Poetz F. Schnolzer M. Voit R. Grummt I. (2017 ). SIRT7-dependent deacetylation of CDK9 activates RNA polymerase II transcription. Nucleic Acids Res. 45 2675–2686.

    Not in our library10.1093/nar/gkx053

  37. 37.

    Bonkowski M. S. Sinclair D. A. (2016 ). Slowing ageing by design: the rise of NAD(+) and sirtuin-activating compounds. Nat. Rev. Mol. Cell Biol. 17 679–690.

    Not in our library10.1038/nrm.2016.93

  38. 38.

    Boucheron N. Tschismarov R. Goeschl L. Moser M. A. Lagger S. Sakaguchi S. (2014 ). CD4(+) T cell lineage integrity is controlled by the histone deacetylases HDAC1 and HDAC2. Nat. Immunol. 15 439–448.

    Not in our library10.1038/ni.2864

  39. 39.

    Bowman C. J. Ayer D. E. Dynlacht B. D. (2014 ). Foxk proteins repress the initiation of starvation-induced atrophy and autophagy programs. Nat. Cell Biol. 16 1202–1214.

    Not in our library10.1038/ncb3062

  40. 40.

    Boyault C. Gilquin B. Zhang Y. Rybin V. Garman E. Meyer-Klaucke W. (2006 ). HDAC6-p97/VCP controlled polyubiquitin chain turnover. EMBO J. 25 3357–3366.

    Not in our library10.1038/sj.emboj.7601210

  41. 41.

    Bradley E. W. Carpio L. R. Olson E. N. Westendorf J. J. (2015 ). Histone deacetylase 7 (Hdac7) suppresses chondrocyte proliferation and beta-catenin activity during endochondral ossification. J. Biol. Chem. 290 118–126.

    Not in our library10.1074/jbc.m114.596247

  42. 42.

    Brautigam L. Jensen L. D. Poschmann G. Nystrom S. Bannenberg S. Dreij K. (2013 ). Glutaredoxin regulates vascular development by reversible glutathionylation of sirtuin 1. Proc. Natl. Acad. Sci. U.S.A. 110 20057–20062.

    Not in our library10.1073/pnas.1313753110

  43. 43.

    Brunet A. Bonni A. Zigmond M. J. Lin M. Z. Juo P. Hu L. S. (1999 ). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96 857–868.

    Not in our library10.1016/s0092-8674(00)80595-4

  44. 44.

    Brunet A. Sweeney L. B. Sturgill J. F. Chua K. F. Greer P. L. Lin Y. (2004 ). Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303 2011–2015.

    Not in our library10.1126/science.1094637

  45. 45.

    Buggy J. J. Sideris M. L. Mak P. Lorimer D. D. Mcintosh B. Clark J. M. (2000 ). Cloning and characterization of a novel human histone deacetylase, HDAC8. Biochem. J. 350(Pt 1), 199–205.

    Not in our library10.1042/bj3500199

  46. 46.

    Burgess A. Ruefli A. Beamish H. Warrener R. Saunders N. Johnstone R. (2004 ). Histone deacetylase inhibitors specifically kill nonproliferating tumour cells. Oncogene 23 6693–6701.

    Not in our library10.1038/sj.onc.1207893

  47. 47.

    Cadot B. Brunetti M. Coppari S. Fedeli S. De Rinaldis E. Dello Russo C. (2009 ). Loss of histone deacetylase 4 causes segregation defects during mitosis of p53-deficient human tumor cells. Cancer Res. 69 6074–6082.

    Not in our library10.1158/0008-5472.can-08-2796

  48. 48.

    Cameron E. E. Bachman K. E. Myohanen S. Herman J. G. Baylin S. B. (1999 ). Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat. Genet. 21 103–107.

    Not in our library10.1038/5047

  49. 49.

    Cao J. Sun L. Aramsangtienchai P. Spiegelman N. A. Zhang X. Huang W. (2019 ). HDAC11 regulates type I interferon signaling through defatty-acylation of SHMT2. Proc. Natl. Acad. Sci. U.S.A. 116 5487–5492.

    Not in our library10.1073/pnas.1815365116

  50. 50.

    Cao L. L. Shen C. Zhu W. G. (2016 ). Histone modifications in DNA damage response. Sci. China Life Sci. 59 257–270.

    Not in our library10.1007/s11427-016-5011-z

  51. 51.

    Carafa V. Nebbioso A. Cuomo F. Rotili D. Cobellis G. Bontempo P. (2018 ). RIP1-HAT1-SIRT complex identification and targeting in treatment and prevention of cancer. Clin. Cancer Res. 24 2886–2900.

    Not in our library10.1158/1078-0432.ccr-17-3081

  52. 52.

    Carafa V. Poziello A. Della Torre L. Giovannelli P. Di Donato M. Safadeh E. (2019 ). Enzymatic and biological characterization of novel sirtuin modulators against cancer. Int. J. Mol. Sci. 20:5654.

    Not in our library10.3390/ijms20225654

  53. 53.
    Sirtuin functions and modulation: from chemistry to the clinic · 2016
    No notice
  54. 54.

    Castaneda C. A. Wolfson N. A. Leng K. R. Kuo Y. M. Andrews A. J. Fierke C. A. (2017 ). HDAC8 substrate selectivity is determined by long- and short-range interactions leading to enhanced reactivity for full-length histone substrates compared with peptides. J. Biol. Chem. 292 21568–21577.

    Not in our library10.1074/jbc.m117.811026

  55. 55.

    Cencioni C. Spallotta F. Savoia M. Kuenne C. Guenther S. Re A. (2018 ). Zeb1-Hdac2-eNOS circuitry identifies early cardiovascular precursors in naive mouse embryonic stem cells. Nat. Commun. 9:1281.

    Not in our library10.1038/s41467-018-03668-0

  56. 56.

    Chalkiadaki A. Guarente L. (2015 ). The multifaceted functions of sirtuins in cancer. Nat. Rev. Cancer 15 608–624.

    Not in our library10.1038/nrc3985

  57. 57.

    Chang S. Young B. D. Li S. Qi X. Richardson J. A. Olson E. N. (2006 ). Histone deacetylase 7 maintains vascular integrity by repressing matrix metalloproteinase 10. Cell 126 321–334.

    Not in our library10.1016/j.cell.2006.05.040

  58. 58.

    Chatterjee T. K. Idelman G. Blanco V. Blomkalns A. L. Piegore M. G. Jr. Weintraub D. S. (2011 ). Histone deacetylase 9 is a negative regulator of adipogenic differentiation. J. Biol. Chem. 286 27836–27847.

    Not in our library10.1074/jbc.m111.262964

  59. 59.

    Chen A. C. Martin A. J. Choy B. Fernandez-Penas P. Dalziell R. A. Mckenzie C. A. (2015 ). A Phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N. Engl. J. Med. 373 1618–1626.

    Not in our library10.1056/nejmoa1506197

  60. 60.

    Chen G. Zhang B. Xu H. Sun Y. Shi Y. Luo Y. (2017 ). Suppression of Sirt1 sensitizes lung cancer cells to WEE1 inhibitor MK-1775-induced DNA damage and apoptosis. Oncogene 36 6863–6872.

    Not in our library10.1038/onc.2017.297

  61. 61.

    Chen L. Zhang Z. Hoshino A. Zheng H. D. Morley M. Arany Z. (2019 ). NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism. Nat. Metab. 1 404–415.

    Not in our library10.1038/s42255-019-0043-x

  62. 62.

    Chen X. Barozzi I. Termanini A. Prosperini E. Recchiuti A. Dalli J. (2012 ). Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages. Proc. Natl. Acad. Sci. U.S.A. 109 E2865–E2874.

    Not in our library10.1073/pnas.1121131109

  63. 63.

    Chen X. F. Tian M. X. Sun R. Q. Zhang M. L. Zhou L. S. Jin L. (2018 ). SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer. EMBO Rep. 19:e45124.

    Not in our library10.15252/embr.201745124

  64. 64.

    Choi S. J. Lee H. C. Kim J. H. Park S. Y. Kim T. H. Lee W. K. (2016 ). HDAC6 regulates cellular viral RNA sensing by deacetylation of RIG-I. EMBO J. 35 429–442.

    Not in our library10.15252/embj.201592586

  65. 65.

    Choy E. Ballman K. Chen J. Dickson M. A. Chugh R. George S. (2019 ). Corrigendum to “SARC018_SPORE02: phase II Study of Mocetinostat Administered with Gemcitabine for Patients with Metastatic Leiomyosarcoma with Progression or Relapse following Prior Treatment with Gemcitabine-Containing Therapy”. Sarcoma 2019:7608743.

    Not in our library10.1155/2019/7608743

  66. 66.

    Cimen H. Han M. J. Yang Y. Tong Q. Koc H. Koc E. C. (2010 ). Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 49 304–311.

    Not in our library10.1021/bi901627u

  67. 67.

    Cohen H. Y. Miller C. Bitterman K. J. Wall N. R. Hekking B. Kessler B. (2004 ). Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305 390–392.

    Not in our library10.1126/science.1099196

  68. 68.

    Conti C. Leo E. Eichler G. S. Sordet O. Martin M. M. Fan A. (2010 ). Inhibition of histone deacetylase in cancer cells slows down replication forks, activates dormant origins, and induces DNA damage. Cancer Res. 70 4470–4480.

    Not in our library10.1158/0008-5472.can-09-3028

  69. 69.

    Cosenza M. Civallero M. Marcheselli L. Sacchi S. Pozzi S. (2017 ). Ricolinostat, a selective HDAC6 inhibitor, shows anti-lymphoma cell activity alone and in combination with bendamustine. Apoptosis 22 827–840.

    Not in our library10.1007/s10495-017-1364-4

  70. 70.

    Costa-Machado L. F. Martin-Hernandez R. Sanchez-Luengo M. A. Hess K. Vales-Villamarin C. Barradas M. (2018 ). Sirt1 protects from K-Ras-driven lung carcinogenesis. EMBO Rep. 19:e43879.

    Not in our library10.15252/embr.201643879

  71. 71.

    Daenthanasanmak A. Iamsawat S. Chakraborty P. Nguyen H. D. Bastian D. Liu C. (2019 ). Targeting Sirt-1 controls GVHD by inhibiting T-cell allo-response and promoting Treg stability in mice. Blood 133 266–279.

    Not in our library10.1182/blood-2018-07-863233

  72. 72.

    Dai H. Sinclair D. A. Ellis J. L. Steegborn C. (2018 ). Sirtuin activators and inhibitors: promises, achievements, and challenges. Pharmacol. Ther. 188 140–154.

    Not in our library10.1016/j.pharmthera.2018.03.004

  73. 73.

    Dai X. Xin Y. Xu W. Tian X. Wei X. Zhang H. (2020 ). CBP-mediated Slug acetylation stabilizes Slug and promotes EMT and migration of breast cancer cells. Sci. China Life Sci. [Epub ahead of print].

    Not in our library10.1007/s11427-020-1736-5

  74. 74.

    Dai Y. Chen S. Kramer L. B. Funk V. L. Dent P. Grant S. (2008 ). Interactions between bortezomib and romidepsin and belinostat in chronic lymphocytic leukemia cells. Clin. Cancer Res. 14 549–558.

    Not in our library10.1158/1078-0432.ccr-07-1934

  75. 75.

    Danko C. G. Hyland S. L. Core L. J. Martins A. L. Waters C. T. Lee H. W. (2015 ). Identification of active transcriptional regulatory elements from GRO-seq data. Nat. Methods 12 433–438.

    Not in our library10.1038/nmeth.3329

  76. 76.

    Dawson M. A. Kouzarides T. (2012 ). Cancer epigenetics: from mechanism to therapy. Cell 150 12–27.

    Not in our library10.1016/j.cell.2012.06.013

  77. 77.

    De U. Son J. Y. Sachan R. Park Y. J. Kang D. Yoon K. (2018 ). A New synthetic histone deacetylase inhibitor, MHY2256, induces apoptosis and autophagy cell death in endometrial cancer cells via p53 acetylation. Int. J. Mol. Sci. 19:2743.

    Not in our library10.3390/ijms19092743

  78. 78.

    Dequiedt F. Martin M. Von Blume J. Vertommen D. Lecomte E. Mari N. (2006 ). New role for hPar-1 kinases EMK and C-TAK1 in regulating localization and activity of class IIa histone deacetylases. Mol. Cell. Biol. 26 7086–7102.

    Not in our library10.1128/mcb.00231-06

  79. 79.

    Dhalluin C. Carlson J. E. Zeng L. He C. Aggarwal A. K. Zhou M. M. (1999 ). Structure and ligand of a histone acetyltransferase bromodomain. Nature 399 491–496.

    Not in our library10.1038/20974

  80. 80.

    Di Giorgio E. Dalla E. Franforte E. Paluvai H. Minisini M. Trevisanut M. (2020 ). Different class IIa HDACs repressive complexes regulate specific epigenetic responses related to cell survival in leiomyosarcoma cells. Nucleic Acids Res. 48 646–664.

    Not in our library10.1093/nar/gkz1120

  81. 81.

    Dioum E. M. Chen R. Alexander M. S. Zhang Q. Hogg R. T. Gerard R. D. (2009 ). Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1. Science 324 1289–1293.

    Not in our library10.1126/science.1169956

  82. 82.

    Dovey O. M. Foster C. T. Conte N. Edwards S. A. Edwards J. M. Singh R. (2013 ). Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice. Blood 121 1335–1344.

    Not in our library10.1182/blood-2012-07-441949

  83. 83.

    Dryden S. C. Nahhas F. A. Nowak J. E. Goustin A. S. Tainsky M. A. (2003 ). Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol. Cell. Biol. 23 3173–3185.

    Not in our library10.1128/mcb.23.9.3173-3185.2003

  84. 84.

    Du J. Zhou Y. Su X. Yu J. J. Khan S. Jiang H. (2011 ). Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334 806–809.

    Not in our library10.1126/science.1207861

  85. 85.

    El-Naggar A. M. Somasekharan S. P. Wang Y. Cheng H. Negri G. L. Pan M. (2019 ). Class I HDAC inhibitors enhance YB-1 acetylation and oxidative stress to block sarcoma metastasis. EMBO Rep. 20:e48375.

    Not in our library10.15252/embr.201948375

  86. 86.

    Emiliani S. Fischle W. Van Lint C. Al-Abed Y. Verdin E. (1998 ). Characterization of a human RPD3 ortholog, HDAC3. Proc. Natl. Acad. Sci. U.S.A. 95 2795–2800.

    Not in our library10.1073/pnas.95.6.2795

  87. 87.

    Emmett M. J. Lazar M. A. (2019 ). Integrative regulation of physiology by histone deacetylase 3. Nat. Rev. Mol. Cell Biol. 20 102–115.

    Not in our library10.1038/s41580-018-0076-0

  88. 88.

    Eom G. H. Nam Y. S. Oh J. G. Choe N. Min H. K. Yoo E. K. (2014 ). Regulation of acetylation of histone deacetylase 2 by p300/CBP-associated factor/histone deacetylase 5 in the development of cardiac hypertrophy. Circ. Res. 114 1133–1143.

    Not in our library10.1161/circresaha.114.303429

  89. 89.

    Eot-Houllier G. Fulcrand G. Watanabe Y. Magnaghi-Jaulin L. Jaulin C. (2008 ). Histone deacetylase 3 is required for centromeric H3K4 deacetylation and sister chromatid cohesion. Genes Dev. 22 2639–2644.

    Not in our library10.1101/gad.484108

  90. 90.

    Etchegaray J. P. Chavez L. Huang Y. Ross K. N. Choi J. Martinez-Pastor B. (2015 ). The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine. Nat. Cell Biol. 17 545–557.

    Not in our library10.1038/ncb3147

  91. 91.

    Etchegaray J. P. Zhong L. Li C. Henriques T. Ablondi E. Nakadai T. (2019 ). The histone deacetylase SIRT6 restrains transcription elongation via promoter-proximal pausing. Mol. Cell 75 683–699.e7.

    Not in our library10.1016/j.molcel.2019.06.034

  92. 92.

    Falkenberg K. J. Johnstone R. W. (2014 ). Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat. Rev. Drug Discov. 13 673–691.

    Not in our library10.1038/nrd4360

  93. 93.

    Fan W. Luo J. (2010 ). SIRT1 regulates UV-induced DNA repair through deacetylating XPA. Mol. Cell 39 247–258.

    Not in our library10.1016/j.molcel.2010.07.006

  94. 94.

    Fang J. Ianni A. Smolka C. Vakhrusheva O. Nolte H. Kruger M. (2017 ). Sirt7 promotes adipogenesis in the mouse by inhibiting autocatalytic activation of Sirt1. Proc. Natl. Acad. Sci. U.S.A. 114 E8352–E8361.

    Not in our library10.1073/pnas.1706945114

  95. 95.

    Feldman J. L. Baeza J. Denu J. M. (2013 ). Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. J. Biol. Chem. 288 31350–31356.

    Not in our library10.1074/jbc.c113.511261

  96. 96.

    Ferrari A. C. Alumkal J. J. Stein M. N. Taplin M. E. Babb J. Barnett E. S. (2019 ). Epigenetic therapy with panobinostat combined with bicalutamide rechallenge in castration-resistant prostate cancer. Clin. Cancer Res. 25 52–63.

    Not in our library10.1158/1078-0432.ccr-18-1589

  97. 97.

    Ferrer C. M. Lu T. Y. Bacigalupa Z. A. Katsetos C. D. Sinclair D. A. Reginato M. J. (2017 ). O-GlcNAcylation regulates breast cancer metastasis via SIRT1 modulation of FOXM1 pathway. Oncogene 36 559–569.

    Not in our library10.1038/onc.2016.228

  98. 98.

    Filippakopoulos P. Knapp S. (2014 ). Targeting bromodomains: epigenetic readers of lysine acetylation. Nat. Rev. Drug Discov. 13 337–356.

    Not in our library10.1038/nrd4286

  99. 99.

    Finley L. W. Carracedo A. Lee J. Souza A. Egia A. Zhang J. (2011 ). SIRT3 opposes reprogramming of cancer Cell Metab.olism through HIF1alpha destabilization. Cancer Cell 19 416–428.

    Not in our library10.1016/j.ccr.2011.02.014

  100. 100.

    Finnin M. S. Donigian J. R. Cohen A. Richon V. M. Rifkind R. A. Marks P. A. (1999 ). Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401 188–193.

    Not in our library10.1038/43710

  101. 101.

    Fischer D. D. Cai R. Bhatia U. Asselbergs F. A. Song C. Terry R. (2002 ). Isolation and characterization of a novel class II histone deacetylase, HDAC10. J. Biol. Chem. 277 6656–6666.

    Not in our library10.1074/jbc.m108055200

  102. 102.

    Fiskus W. Coothankandaswamy V. Chen J. Ma H. Ha K. Saenz D. T. (2016 ). SIRT2 deacetylates and inhibits the peroxidase activity of peroxiredoxin-1 to sensitize breast cancer cells to oxidant stress-inducing agents. Cancer Res. 76 5467–5478.

    Not in our library10.1158/0008-5472.can-16-0126

  103. 103.

    Foss F. Advani R. Duvic M. Hymes K. B. Intragumtornchai T. Lekhakula A. (2015 ). A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma. Br. J. Haematol. 168 811–819.

    Not in our library10.1111/bjh.13222

  104. 104.

    Fujisawa T. Filippakopoulos P. (2017 ). Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat. Rev. Mol. Cell Biol. 18 246–262.

    Not in our library10.1038/nrm.2016.143

  105. 105.

    Fukumoto T. Park P. H. Wu S. Fatkhutdinov N. Karakashev S. Nacarelli T. (2018 ). Repurposing Pan-HDAC inhibitors for ARID1A-mutated ovarian cancer. Cell Rep. 22 3393–3400.

    Not in our library10.1016/j.celrep.2018.03.019

  106. 106.

    Funato K. Hayashi T. Echizen K. Negishi L. Shimizu N. Koyama-Nasu R. (2018 ). SIRT2-mediated inactivation of p73 is required for glioblastoma tumorigenicity. EMBO Rep. 19:e4558.

    Not in our library10.15252/embr.201745587

  107. 107.

    Fyodorov D. V. Zhou B. R. Skoultchi A. I. Bai Y. (2018 ). Emerging roles of linker histones in regulating chromatin structure and function. Nat. Rev. Mol. Cell Biol. 19 192–206.

    Not in our library10.1038/nrm.2017.94

  108. 108.

    Galloway T. J. Wirth L. J. Colevas A. D. Gilbert J. Bauman J. E. Saba N. F. (2015 ). A Phase I Study of CUDC-101, a Multitarget Inhibitor of HDACs, EGFR, and HER2, in Combination with Chemoradiation in Patients with Head and Neck Squamous Cell Carcinoma. Clin. Cancer Res. 21 1566–1573.

    Not in our library10.1158/1078-0432.ccr-14-2820

  109. 109.

    Gammoh N. Lam D. Puente C. Ganley I. Marks P. A. Jiang X. (2012 ). Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death. Proc. Natl. Acad. Sci. U.S.A. 109 6561–6565.

    Not in our library10.1073/pnas.1204429109

  110. 110.

    Gao C. Ho C. C. Reineke E. Lam M. Cheng X. Stanya K. J. (2008 ). Histone deacetylase 7 promotes PML sumoylation and is essential for PML nuclear body formation. Mol. Cell. Biol. 28 5658–5667.

    Not in our library10.1128/mcb.00874-08

  111. 111.

    Gao L. Cueto M. A. Asselbergs F. Atadja P. (2002 ). Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J. Biol. Chem. 277 25748–25755.

    Not in our library10.1074/jbc.m111871200

  112. 112.

    Gao Y. S. Hubbert C. C. Lu J. Lee Y. S. Lee J. Y. Yao T. P. (2007 ). Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis. Mol. Cell. Biol. 27 8637–8647.

    Not in our library10.1128/mcb.00393-07

  113. 113.

    Ginsburg E. Salomon D. Sreevalsan T. Freese E. (1973 ). Growth inhibition and morphological changes caused by lipophilic acids in mammalian cells. Proc. Natl. Acad. Sci. U.S.A. 70 2457–2461.

    Not in our library10.1073/pnas.70.8.2457

  114. 114.

    Glozak M. A. Seto E. (2007 ). Histone deacetylases and cancer. Oncogene 26 5420–5432.

    Not in our library10.1038/sj.onc.1210610

  115. 115.

    Goder A. Emmerich C. Nikolova T. Kiweler N. Schreiber M. Kuhl T. (2018 ). HDAC1 and HDAC2 integrate checkpoint kinase phosphorylation and cell fate through the phosphatase-2A subunit PR130. Nat. Commun. 9:764.

    Not in our library10.1038/s41467-018-03096-0

  116. 116.

    Gonzalez F. J. Xie C. Jiang C. (2018 ). The role of hypoxia-inducible factors in metabolic diseases. Nat. Rev. Endocrinol. 15 21–32.

    Not in our library10.1038/s41574-018-0096-z

  117. 117.

    Gorisch S. M. Wachsmuth M. Toth K. F. Lichter P. Rippe K. (2005 ). Histone acetylation increases chromatin accessibility. J. Cell Sci. 118 5825–5834.

    Not in our library10.1242/jcs.02689

  118. 118.

    Greene K. S. Lukey M. J. Wang X. Blank B. Druso J. E. Lin M. J. (2019 ). SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis. Proc. Natl. Acad. Sci. U.S.A. 116 26625–26632.

    Not in our library10.1073/pnas.1911954116

  119. 119.

    Greer C. B. Tanaka Y. Kim Y. J. Xie P. Zhang M. Q. Park I. H. (2015 ). Histone deacetylases positively regulate transcription through the elongation machinery. Cell Rep. 13 1444–1455.

    Not in our library10.1016/j.celrep.2015.10.013

  120. 120.

    Grozinger C. M. Hassig C. A. Schreiber S. L. (1999 ). Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proc. Natl. Acad. Sci. U.S.A. 96 4868–4873.

    Not in our library10.1073/pnas.96.9.4868

  121. 121.
    Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3- 3-dependent cellular localization · 2000
    Not checked
  122. 122.

    Grunstein M. (1997 ). Histone acetylation in chromatin structure and transcription. Nature 389 349–352.

    Not in our library10.1038/38664

  123. 123.
    Chemical genomics reveals histone deacetylases are required for core regulatory transcription · 2019
    No notice
  124. 124.

    Gu B. Zhu W. G. (2012 ). Surf the post-translational modification network of p53 regulation. Int. J. Biol. Sci. 8 672–684.

    Not in our library10.7150/ijbs.4283

  125. 125.

    Gu W. Roeder R. G. (1997 ). Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90 595–606.

    Not in our library10.1016/s0092-8674(00)80521-8

  126. 126.

    Guardiola A. R. Yao T. P. (2002 ). Molecular cloning and characterization of a novel histone deacetylase HDAC10. J. Biol. Chem. 277 3350–3356.

    Not in our library10.1074/jbc.m109861200

  127. 127.

    Guerriero J. L. Sotayo A. Ponichtera H. E. Castrillon J. A. Pourzia A. L. Schad S. (2017 ). Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature 543 428–432.

    Not in our library10.1038/nature21409

  128. 128.

    Guo C. Zhao Y. (2020 ). Autophagy and DNA damage repair. Genome Instabil. Dis. 1 172–183.

    Not in our library10.1007/s42764-020-00016-9

  129. 129.

    Guo H. Zeng D. Zhang H. Bell T. Yao J. Liu Y. (2019 ). Dual inhibition of PI3K signaling and histone deacetylation halts proliferation and induces lethality in mantle cell lymphoma. Oncogene 38 1802–1814.

    Not in our library10.1038/s41388-018-0550-3

  130. 130.

    Guo L. Zhou S. R. Wei X. B. Liu Y. Chang X. X. Liu Y. (2016 ). Acetylation of mitochondrial trifunctional protein alpha-subunit enhances its stability to promote fatty acid oxidation and is decreased in nonalcoholic fatty liver disease. Mol. Cell. Biol. 36 2553–2567.

    Not in our library10.1128/mcb.00227-16

  131. 131.

    Guo Q. Li F. Duan Y. Wen C. Wang W. Zhang L. (2020 ). Oxidative stress, nutritional antioxidants and beyond. Sci. China Life Sci. 63 866–874.

    Not in our library10.1007/s11427-019-9591-5

  132. 132.

    Haberland M. Johnson A. Mokalled M. H. Montgomery R. L. Olson E. N. (2009 ). Genetic dissection of histone deacetylase requirement in tumor cells. Proc. Natl. Acad. Sci. U.S.A. 106 7751–7755.

    Not in our library10.1073/pnas.0903139106

  133. 133.

    Hai Y. Christianson D. W. (2016 ). Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. Nat. Chem. Biol. 12 741–747.

    Not in our library10.1038/nchembio.2134

  134. 134.
    Histone deacetylase 10 structure and molecular function as a polyamine deacetylase · 2017
    No notice
  135. 135.

    Haigis M. C. Mostoslavsky R. Haigis K. M. Fahie K. Christodoulou D. C. Murphy A. J. (2006 ). SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126 941–954.

    Not in our library10.1016/j.cell.2006.06.057

  136. 136.

    Harms K. L. Chen X. (2007 ). Histone deacetylase 2 modulates p53 transcriptional activities through regulation of p53-DNA binding activity. Cancer Res. 67 3145–3152.

    Not in our library10.1158/0008-5472.can-06-4397

  137. 137.

    Hassig C. A. Fleischer T. C. Billin A. N. Schreiber S. L. Ayer D. E. (1997 ). Histone deacetylase activity is required for full transcriptional repression by mSin3A. Cell 89 341–347.

    Not in our library10.1016/s0092-8674(00)80214-7

  138. 138.

    Heideman M. R. Wilting R. H. Yanover E. Velds A. De Jong J. Kerkhoven R. M. (2013 ). Dosage-dependent tumor suppression by histone deacetylases 1 and 2 through regulation of c-Myc collaborating genes and p53 function. Blood 121 2038–2050.

    Not in our library10.1182/blood-2012-08-450916

  139. 139.

    Hershberger K. A. Abraham D. M. Liu J. Locasale J. W. Grimsrud P. A. Hirschey M. D. (2018 ). Ablation of Sirtuin5 in the postnatal mouse heart results in protein succinylation and normal survival in response to chronic pressure overload. J. Biol. Chem. 293 10630–10645.

    Not in our library10.1074/jbc.ra118.002187

  140. 140.

    Hideshima T. Bradner J. E. Wong J. Chauhan D. Richardson P. Schreiber S. L. (2005 ). Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc. Natl. Acad. Sci. U.S.A. 102 8567–8572.

    Not in our library10.1073/pnas.0503221102

  141. 141.

    Hideshima T. Qi J. Paranal R. M. Tang W. Greenberg E. West N. (2016 ). Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma. Proc. Natl. Acad. Sci. U.S.A. 113 13162–13167.

    Not in our library10.1073/pnas.1608067113

  142. 142.

    Hirschey M. D. Shimazu T. Goetzman E. Jing E. Schwer B. Lombard D. B. (2010 ). SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464 121–125.

    Not in our library10.1038/nature08778

  143. 143.

    Ho M. Chen T. Liu J. Dowling P. Hideshima T. Zhang L. (2020 ). Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signaling. Leukemia 34 196–209.

    Not in our library10.1038/s41375-019-0493-x

  144. 144.

    Hook S. S. Orian A. Cowley S. M. Eisenman R. N. (2002 ). Histone deacetylase 6 binds polyubiquitin through its zinc finger (PAZ domain) and copurifies with deubiquitinating enzymes. Proc. Natl. Acad. Sci. U.S.A. 99 13425–13430.

    Not in our library10.1073/pnas.172511699

  145. 145.

    Hou T. Cao Z. Zhang J. Tang M. Tian Y. Li Y. (2020 ). SIRT6 coordinates with CHD4 to promote chromatin relaxation and DNA repair. Nucleic Acids Res. 48 2982–3000.

    Not in our library10.1093/nar/gkaa006

  146. 146.

    Houtkooper R. H. Pirinen E. Auwerx J. (2012 ). Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13 225–238.

    Not in our library10.1038/nrm3293

  147. 147.

    Howitz K. T. Bitterman K. J. Cohen H. Y. Lamming D. W. Lavu S. Wood J. G. (2003 ). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425 191–196.

    Not in our library10.1038/nature01960

  148. 148.

    Hsia D. A. Tepper C. G. Pochampalli M. R. Hsia E. Y. Izumiya C. Huerta S. B. (2010 ). KDM8, a H3K36me2 histone demethylase that acts in the cyclin A1 coding region to regulate cancer cell proliferation. Proc. Natl. Acad. Sci. U.S.A. 107 9671–9676.

    Not in our library10.1073/pnas.1000401107

  149. 149.

    Hsieh C. L. Fei T. Chen Y. Li T. Gao Y. Wang X. (2014 ). Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation. Proc. Natl. Acad. Sci. U.S.A. 111 7319–7324.

    Not in our library10.1073/pnas.1324151111

  150. 150.

    Hsu F. C. Belmonte P. J. Constans M. M. Chen M. W. Mcwilliams D. C. Hiebert S. W. (2015 ). Histone Deacetylase 3 Is Required for T Cell Maturation. J. Immunol. 195 1578–1590.

    Not in our library10.4049/jimmunol.1500435

  151. 151.

    Hu E. Chen Z. Fredrickson T. Zhu Y. Kirkpatrick R. Zhang G. F. (2000 ). Cloning and characterization of a novel human class I histone deacetylase that functions as a transcription repressor. J. Biol. Chem. 275 15254–15264.

    Not in our library10.1074/jbc.m908988199

  152. 152.

    Hu F. Sun X. Li G. Wu Q. Chen Y. Yang X. (2018 ). Inhibition of SIRT2 limits tumour angiogenesis via inactivation of the STAT3/VEGFA signalling pathway. Cell Death Dis. 10:9.

    Not in our library10.1038/s41419-018-1260-z

  153. 153.

    Hu T. Schreiter F. C. Bagchi R. A. Tatman P. D. Hannink M. Mckinsey T. A. (2019 ). HDAC5 catalytic activity suppresses cardiomyocyte oxidative stress and NRF2 target gene expression. J. Biol. Chem. 294 8640–8652.

    Not in our library10.1074/jbc.ra118.007006

  154. 154.

    Hua W. K. Qi J. Cai Q. Carnahan E. Ayala Ramirez M. Li L. (2017 ). HDAC8 regulates long-term hematopoietic stem-cell maintenance under stress by modulating p53 activity. Blood 130 2619–2630.

    Not in our library10.1182/blood-2017-03-771386

  155. 155.

    Huang F. Sun J. Chen W. He X. Zhu Y. Dong H. (2020 ). HDAC4 inhibition disrupts TET2 function in high-risk MDS and AML. Aging. [Epub ahead of print].

    Not in our library10.18632/aging.103605

  156. 156.

    Huang H. Sabari B. R. Garcia B. A. Allis C. D. Zhao Y. (2014 ). SnapShot: histone modifications. Cell 159 458–458.e1.

    Not in our library10.1016/j.cell.2014.09.037

  157. 157.
    Lysine benzoylation is a histone mark regulated by SIRT2 · 2018
    No notice
  158. 158.

    Huang Z. Zhao J. Deng W. Chen Y. Shang J. Song K. (2018b ). Identification of a cellularly active SIRT6 allosteric activator. Nat. Chem. Biol. 14 1118–1126.

    Not in our library10.1038/s41589-018-0150-0

  159. 159.

    Huang Z. Zhou W. Li Y. Cao M. Wang T. Ma Y. (2018c ). Novel hybrid molecule overcomes the limited response of solid tumours to HDAC inhibitors via suppressing JAK1-STAT3-BCL2 signalling. Theranostics 8 4995–5011.

    Not in our library10.7150/thno.26627

  160. 160.

    Hubbard B. P. Gomes A. P. Dai H. Li J. Case A. W. Considine T. (2013 ). Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339 1216–1219.

    Not in our library10.1126/science.1231097

  161. 161.

    Hubbert C. Guardiola A. Shao R. Kawaguchi Y. Ito A. Nixon A. (2002 ). HDAC6 is a microtubule-associated deacetylase. Nature 417 455–458.

    Not in our library10.1038/417455a

  162. 162.

    Hubbi M. E. Hu H. Kshitiz, Gilkes D. M. Semenza G. L. (2013 ). Sirtuin-7 inhibits the activity of hypoxia-inducible factors. J. Biol. Chem. 288 20768–20775.

    Not in our library10.1074/jbc.m113.476903

  163. 163.

    Humphrey G. W. Wang Y. Russanova V. R. Hirai T. Qin J. Nakatani Y. (2001 ). Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1. J. Biol. Chem. 276 6817–6824.

    Not in our library10.1074/jbc.m007372200

  164. 164.

    Igase M. Fujiki N. Shibutani S. Sakai H. Noguchi S. Nemoto Y. (2020 ). Tenovin-6 induces the SIRT-independent cell growth suppression and blocks autophagy flux in canine hemangiosarcoma cell lines. Exp. Cell Res. 388:111810.

    Not in our library10.1016/j.yexcr.2019.111810

  165. 165.

    Imai S. Armstrong C. M. Kaeberlein M. Guarente L. (2000 ). Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403 795–800.

    Not in our library10.1038/35001622

  166. 166.

    Imai S. Guarente L. (2014 ). NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24 464–471.

    Not in our library10.1016/j.tcb.2014.04.002

  167. 167.

    Ingham O. J. Paranal R. M. Smith W. B. Escobar R. A. Yueh H. Snyder T. (2016 ). Development of a potent and selective HDAC8 inhibitor. ACS Med. Chem. Lett. 7 929–932.

    Not in our library10.1021/acsmedchemlett.6b00239

  168. 168.

    Inoue A. Fujimoto D. (1969 ). Enzymatic deacetylation of histone. Biochem. Biophys. Res. Commun. 36 146–150.

    Not in our library10.1016/0006-291x(69)90661-5

  169. 169.

    Itazaki H. Nagashima K. Sugita K. Yoshida H. Kawamura Y. Yasuda Y. (1990 ). Isolation and structural elucidation of new cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor agents. J. Antibiot. 43 1524–1532.

    Not in our library10.7164/antibiotics.43.1524

  170. 170.

    Itoh T. Fairall L. Muskett F. W. Milano C. P. Watson P. J. Arnaudo N. (2015 ). Structural and functional characterization of a cell cycle associated HDAC1/2 complex reveals the structural basis for complex assembly and nucleosome targeting. Nucleic Acids Res. 43 2033–2044.

    Not in our library10.1093/nar/gkv068

  171. 171.

    Jackson S. P. Bartek J. (2009 ). The DNA-damage response in human biology and disease. Nature 461 1071–1078.

    Not in our library10.1038/nature08467

  172. 172.

    Jamaladdin S. Kelly R. D. O’regan L. Dovey O. M. Hodson G. E. Millard C. J. (2014 ). Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells. Proc. Natl. Acad. Sci. U.S.A. 111 9840–9845.

    Not in our library10.1073/pnas.1321330111

  173. 173.

    Jarrett S. G. Carter K. M. Bautista R. M. He D. Wang C. D’orazio J. A. (2018 ). Sirtuin 1-mediated deacetylation of XPA DNA repair protein enhances its interaction with ATR protein and promotes cAMP-induced DNA repair of UV damage. J. Biol. Chem. 293 19025–19037.

    Not in our library10.1074/jbc.ra118.003940

  174. 174.

    Jedrusik-Bode M. Studencka M. Smolka C. Baumann T. Schmidt H. Kampf J. (2013 ). The sirtuin SIRT6 regulates stress granule formation in C. elegans and mammals. J. Cell Sci. 126 5166–5177.

    Not in our library10.1242/jcs.130708

  175. 175.

    Jenuwein T. Allis C. D. (2001 ). Translating the histone code. Science 293 1074–1080.

    Not in our library10.1126/science.1063127

  176. 176.

    Jeong S. M. Lee A. Lee J. Haigis M. C. (2014 ). SIRT4 protein suppresses tumor formation in genetic models of Myc-induced B cell lymphoma. J. Biol. Chem. 289 4135–4144.

    Not in our library10.1074/jbc.m113.525949

  177. 177.

    Jeong S. M. Xiao C. Finley L. W. Lahusen T. Souza A. L. Pierce K. (2013 ). SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell 23 450–463.

    Not in our library10.1016/j.ccr.2013.02.024

  178. 178.

    Ji H. Zhou Y. Zhuang X. Zhu Y. Wu Z. Lu Y. (2019 ). HDAC3 deficiency promotes liver cancer through a defect in H3K9ac/H3K9me3 transition. Cancer Res. 79 3676–3688.

    Not in our library10.1158/0008-5472.can-18-3767

  179. 179.

    Jiang H. Khan S. Wang Y. Charron G. He B. Sebastian C. (2013 ). SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496 110–113.

    Not in our library10.1038/nature12038

  180. 180.

    Jiang Y. Hsieh J. (2014 ). HDAC3 controls gap 2/mitosis progression in adult neural stem/progenitor cells by regulating CDK1 levels. Proc. Natl. Acad. Sci. U.S.A. 111 13541–13546.

    Not in our library10.1073/pnas.1411939111

  181. 181.

    Jiang Z. Li W. Hu X. Zhang Q. Sun T. Cui S. (2019 ). Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 20 806–815.

    Not in our library10.1016/s1470-2045(19)30164-0

  182. 182.

    Jin X. Yan Y. Wang D. Ding D. Ma T. Ye Z. (2018 ). DUB3 Promotes BET inhibitor resistance and cancer progression by deubiquitinating BRD4. Mol. Cell 71 592–605.e4.

    Not in our library10.1016/j.molcel.2018.06.036

  183. 183.

    Jing H. Hu J. He B. Negron Abril Y. L. Stupinski J. Weiser K. (2016 ). A SIRT2-selective inhibitor promotes c-Myc oncoprotein degradation and exhibits broad anticancer activity. Cancer Cell 29 297–310.

    Not in our library10.1016/j.ccell.2016.02.007

  184. 184.

    Jones P. A. Issa J. P. Baylin S. (2016 ). Targeting the cancer epigenome for therapy. Nat. Rev. Genet. 17 630–641.

    Not in our library10.1038/nrg.2016.93

  185. 185.

    Jones P. L. Veenstra G. J. Wade P. A. Vermaak D. Kass S. U. Landsberger N. (1998 ). Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat. Genet. 19 187–191.

    Not in our library10.1038/561

  186. 186.

    Juan L. J. Shia W. J. Chen M. H. Yang W. M. Seto E. Lin Y. S. (2000 ). Histone deacetylases specifically down-regulate p53-dependent gene activation. J. Biol. Chem. 275 20436–20443.

    Not in our library10.1074/jbc.m000202200

  187. 187.
    Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors · 2018
    No notice
  188. 188.

    Kaliszczak M. Van Hechanova E. Li Y. Alsadah H. Parzych K. Auner H. W. (2018 ). The HDAC6 inhibitor C1A modulates autophagy substrates in diverse cancer cells and induces cell death. Br. J. Cancer 119 1278–1287.

    Not in our library10.1038/s41416-018-0232-5

  189. 189.

    Kaluza D. Kroll J. Gesierich S. Yao T. P. Boon R. A. Hergenreider E. (2011 ). Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin. EMBO J. 30 4142–4156.

    Not in our library10.1038/emboj.2011.298

  190. 190.

    Kang H. Oka S. Lee D. Y. Park J. Aponte A. M. Jung Y. S. (2017 ). Sirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins. Nat. Commun. 8:15560.

    Not in our library10.1038/ncomms15560

  191. 191.

    Kang J. Y. Kim J. Y. Kim K. B. Park J. W. Cho H. Hahm J. Y. (2018 ). KDM2B is a histone H3K79 demethylase and induces transcriptional repression via sirtuin-1-mediated chromatin silencing. FASEB J. 32 5737–5750.

    Not in our library10.1096/fj.201800242r

  192. 192.

    Kao H. Y. Downes M. Ordentlich P. Evans R. M. (2000 ). Isolation of a novel histone deacetylase reveals that class I and class II deacetylases promote SMRT-mediated repression. Genes Dev. 14 55–66.

    Not in our library

  193. 193.

    Kao H. Y. Lee C. H. Komarov A. Han C. C. Evans R. M. (2002 ). Isolation and characterization of mammalian HDAC10, a novel histone deacetylase. J. Biol. Chem. 277 187–193.

    Not in our library10.1074/jbc.m108931200

  194. 194.

    Kasler H. G. Young B. D. Mottet D. Lim H. W. Collins A. M. Olson E. N. (2011 ). Histone deacetylase 7 regulates cell survival and TCR signaling in CD4/CD8 double-positive thymocytes. J. Immunol. 186 4782–4793.

    Not in our library10.4049/jimmunol.1001179

  195. 195.

    Kawaguchi Y. Kovacs J. J. Mclaurin A. Vance J. M. Ito A. Yao T. P. (2003 ). The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115 727–738.

    Not in our library10.1016/s0092-8674(03)00939-5

  196. 196.

    Kim D. J. Dunleavey J. M. Xiao L. Ollila D. W. Troester M. A. Otey C. A. (2018 ). Suppression of TGFbeta-mediated conversion of endothelial cells and fibroblasts into cancer associated (myo)fibroblasts via HDAC inhibition. Br. J. Cancer 118 1359–1368.

    Not in our library10.1038/s41416-018-0072-3

  197. 197.

    Kim G. D. Choi Y. H. Dimtchev A. Jeong S. J. Dritschilo A. Jung M. (1999 ). Sensing of ionizing radiation-induced DNA damage by ATM through interaction with histone deacetylase. J. Biol. Chem. 274 31127–31130.

    Not in our library10.1074/jbc.274.44.31127

  198. 198.

    Kim H. S. Patel K. Muldoon-Jacobs K. Bisht K. S. Aykin-Burns N. Pennington J. D. (2010 ). SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17 41–52.

    Not in our library10.1016/j.ccr.2009.11.023

  199. 199.

    Kim H. S. Vassilopoulos A. Wang R. H. Lahusen T. Xiao Z. Xu X. (2011 ). SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 20 487–499.

    Not in our library10.1016/j.ccr.2011.09.004

  200. 200.

    Kim J. E. Chen J. Lou Z. (2008 ). DBC1 is a negative regulator of SIRT1. Nature 451 583–586.

    Not in our library10.1038/nature06500

  201. 201.

    Kim J. H. Kim D. Cho S. J. Jung K. Y. Kim J. H. Lee J. M. (2019 ). Identification of a novel SIRT7 inhibitor as anticancer drug candidate. Biochem. Biophys. Res. Commun. 508 451–457.

    Not in our library10.1016/j.bbrc.2018.11.120

  202. 202.

    Kim J. J. Lee S. Y. Miller K. M. (2019 ). Preserving genome integrity and function: the DNA damage response and histone modifications. Crit. Rev. Biochem. Mol. Biol. 54 208–241.

    Not in our library10.1080/10409238.2019.1620676

  203. 203.

    Kim K. Skora A. D. Li Z. Liu Q. Tam A. J. Blosser R. L. (2014 ). Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc. Natl. Acad. Sci. U.S.A. 111 11774–11779.

    Not in our library10.1073/pnas.1410626111

  204. 204.

    Kim K. K. Sheppard D. Chapman H. A. (2018 ). TGF-beta1 signaling and tissue fibrosis. Cold Spring Harb. Perspect. Biol. 10:a022293.

    Not in our library10.1101/cshperspect.a022293

  205. 205.

    Kim M. S. Kwon H. J. Lee Y. M. Baek J. H. Jang J. E. Lee S. W. (2001 ). Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat. Med. 7 437–443.

    Not in our library10.1038/86507

  206. 206.

    Kim Y. H. Bagot M. Pinter-Brown L. Rook A. H. Porcu P. Horwitz S. M. (2018 ). Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 19 1192–1204.

    Not in our library10.1016/s1470-2045(18)30379-6

  207. 207.

    Kiran S. Chatterjee N. Singh S. Kaul S. C. Wadhwa R. Ramakrishna G. (2013 ). Intracellular distribution of human SIRT7 and mapping of the nuclear/nucleolar localization signal. FEBS J. 280 3451–3466.

    Not in our library10.1111/febs.12346

  208. 208.

    Kosciuczuk E. M. Mehrotra S. Saleiro D. Kroczynska B. Majchrzak-Kita B. Lisowski P. (2019 ). Sirtuin 2-mediated deacetylation of cyclin-dependent kinase 9 promotes STAT1 signaling in type I interferon responses. J. Biol. Chem. 294 827–837.

    Not in our library10.1074/jbc.ra118.005956

  209. 209.

    Kotian S. Zhang L. Boufraqech M. Gaskins K. Gara S. K. Quezado M. (2017 ). Dual Inhibition of HDAC and tyrosine kinase signaling pathways with CUDC-907 inhibits thyroid cancer growth and metastases. Clin. Cancer Res. 23 5044–5054.

    Not in our library10.1158/1078-0432.ccr-17-1043

  210. 210.

    Kronlage M. Dewenter M. Grosso J. Fleming T. Oehl U. Lehmann L. H. (2019 ). O-GlcNAcylation of histone deacetylase 4 protects the diabetic heart from failure. Circulation 140 580–594.

    Not in our library10.1161/circulationaha.117.031942

  211. 211.

    Krug L. M. Kindler H. L. Calvert H. Manegold C. Tsao A. S. Fennell D. (2015 ). Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Oncol. 16 447–456.

    Not in our library10.1016/s1470-2045(15)70056-2

  212. 212.

    Kugel S. Sebastian C. Fitamant J. Ross K. N. Saha S. K. Jain E. (2016 ). SIRT6 suppresses pancreatic cancer through control of Lin28b. Cell 165 1401–1415.

    Not in our library10.1016/j.cell.2016.04.033

  213. 213.

    Kurdistani S. K. Robyr D. Tavazoie S. Grunstein M. (2002 ). Genome-wide binding map of the histone deacetylase Rpd3 in yeast. Nat. Genet. 31 248–254.

    Not in our library10.1038/ng907

  214. 214.

    Kutateladze T. G. (2011 ). SnapShot: histone readers. Cell 146 842–842.e1.

    Not in our library10.1016/j.cell.2011.08.022

  215. 215.

    Kutil Z. Mikesova J. Zessin M. Meleshin M. Novakova Z. Alquicer G. (2019 ). Continuous activity assay for HDAC11 enabling reevaluation of HDAC inhibitors. ACS Omega 4 19895–19904.

    Not in our library10.1021/acsomega.9b02808

  216. 216.

    Kutil Z. Novakova Z. Meleshin M. Mikesova J. Schutkowski M. Barinka C. (2018 ). Histone Deacetylase 11 Is a Fatty-Acid Deacylase. ACS Chem. Biol. 13 685–693.

    Not in our library10.1021/acschembio.7b00942

  217. 217.

    Kuzmichev A. Margueron R. Vaquero A. Preissner T. S. Scher M. Kirmizis A. (2005 ). Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation. Proc. Natl. Acad. Sci. U.S.A. 102 1859–1864.

    Not in our library10.1073/pnas.0409875102

  218. 218.

    Laherty C. D. Yang W. M. Sun J. M. Davie J. R. Seto E. Eisenman R. N. (1997 ). Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression. Cell 89 349–356.

    Not in our library10.1016/s0092-8674(00)80215-9

  219. 219.

    Lahm A. Paolini C. Pallaoro M. Nardi M. C. Jones P. Neddermann P. (2007 ). Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc. Natl. Acad. Sci. U.S.A. 104 17335–17340.

    Not in our library10.1073/pnas.0706487104

  220. 220.

    Lain S. Hollick J. J. Campbell J. Staples O. D. Higgins M. Aoubala M. (2008 ). Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13 454–463.

    Not in our library10.1016/j.ccr.2008.03.004

  221. 221.

    Lascano S. Lopez M. Arimondo P. B. (2018 ). Natural products and chemical biology tools: alternatives to target epigenetic mechanisms in cancers. Chem. Rec. 18 1854–1876.

    Not in our library10.1002/tcr.201800133

  222. 222.

    Lee E. Furukubo T. Miyabe T. Yamauchi A. Kariya K. (1996 ). Involvement of histone hyperacetylation in triggering DNA fragmentation of rat thymocytes undergoing apoptosis. FEBS Lett. 395 183–187.

    Not in our library10.1016/0014-5793(96)01033-2

  223. 223.

    Lee I. H. Cao L. Mostoslavsky R. Lombard D. B. Liu J. Bruns N. E. (2008 ). A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc. Natl. Acad. Sci. U.S.A. 105 3374–3379.

    Not in our library10.1073/pnas.0712145105

  224. 224.

    Lee J. H. Choy M. L. Ngo L. Venta-Perez G. Marks P. A. (2011 ). Role of checkpoint kinase 1 (Chk1) in the mechanisms of resistance to histone deacetylase inhibitors. Proc. Natl. Acad. Sci. U.S.A. 108 19629–19634.

    Not in our library10.1073/pnas.1117544108

  225. 225.

    Lee M. G. Wynder C. Cooch N. Shiekhattar R. (2005 ). An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 437 432–435.

    Not in our library10.1038/nature04021

  226. 226.

    Lehmann L. H. Jebessa Z. H. Kreusser M. M. Horsch A. He T. Kronlage M. (2018 ). A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway. Nat. Med. 24 62–72.

    Not in our library10.1038/nm.4452

  227. 227.

    Lei Y. Liu L. Zhang S. Guo S. Li X. Wang J. (2017 ). Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation. Mol. Cancer 16:170.

    Not in our library10.1186/s12943-017-0736-2

  228. 228.
    Histone deacetylase 11 inhibition promotes breast cancer metastasis from lymph nodes · 2019
    Not checked
  229. 229.

    Li D. Marchenko N. D. Moll U. M. (2011 ). SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis. Cell Death Differ. 18 1904–1913.

    Not in our library10.1038/cdd.2011.71

  230. 230.

    Li H. Tian Z. Qu Y. Yang Q. Guan H. Shi B. (2019 ). SIRT7 promotes thyroid tumorigenesis through phosphorylation and activation of Akt and p70S6K1 via DBC1/SIRT1 axis. Oncogene 38 345–359.

    Not in our library10.1038/s41388-018-0434-6

  231. 231.
    SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability · 2016
    No notice
  232. 232.

    Li L. Wang L. Li L. Wang Z. Ho Y. Mcdonald T. (2012 ). Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 21 266–281.

    Not in our library10.1016/j.ccr.2011.12.020

  233. 233.

    Li M. Chiang Y. L. Lyssiotis C. A. Teater M. R. Hong J. Y. Shen H. (2019 ). Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis. Cancer Cell 35 916–931.e9.

    Not in our library10.1016/j.ccell.2019.05.002

  234. 234.

    Li M. Hou T. Gao T. Lu X. Yang Q. Zhu Q. (2018 ). p53 cooperates with SIRT6 to regulate cardiolipin de novo biosynthesis. Cell Death Dis. 9:941.

    Not in our library10.1038/s41419-018-0984-0

  235. 235.

    Li Y. Peng L. Seto E. (2015 ). Histone deacetylase 10 regulates the cell cycle G2/M phase transition via a novel Let-7-HMGA2-Cyclin A2 Pathway. Mol. Cell Biol 35 3547–3565.

    Not in our library10.1128/mcb.00400-15

  236. 236.

    Li Y. Seto E. (2016 ). HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb. Perspect. Med. 6:a026831.

    Not in our library10.1101/cshperspect.a026831

  237. 237.

    Li Y. Zhang X. Zhu S. Dejene E. A. Peng W. Sepulveda A. (2020 ). HDAC10 Regulates Cancer Stem-like Cell Properties in KRAS-driven Lung Adenocarcinoma. Cancer Res. 80 3265–3278.

    Not in our library10.1158/0008-5472.can-19-3613

  238. 238.

    Li Z. Chen Y. Tang M. Li Y. Zhu W.-G. (2019 ). Regulation of DNA damage-induced ATM activation by histone modifications. Genome Instabil. Dis. 1 20–33.

    Not in our library10.1007/s42764-019-00004-8

  239. 239.

    Li Z. Zhu W. G. (2014 ). Targeting histone deacetylases for cancer therapy: from molecular mechanisms to clinical implications. Int. J. Biol. Sci. 10 757–770.

    Not in our library10.7150/ijbs.9067

  240. 240.

    Lim B. Murthy R. K. Lee J. Jackson S. A. Iwase T. Davis D. W. (2019 ). A phase Ib study of entinostat plus lapatinib with or without trastuzumab in patients with HER2-positive metastatic breast cancer that progressed during trastuzumab treatment. Br. J. Cancer 120 1105–1112.

    Not in our library10.1038/s41416-019-0473-y

  241. 241.

    Lim J. H. Lee Y. M. Chun Y. S. Chen J. Kim J. E. Park J. W. (2010 ). Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol. Cell 38 864–878.

    Not in our library10.1016/j.molcel.2010.05.023

  242. 242.

    Lin C. L. Tsai M. L. Lin C. Y. Hsu K. W. Hsieh W. S. Chi W. M. (2019 ). HDAC1 and HDAC2 double knockout triggers cell apoptosis in advanced thyroid cancer. Int. J. Mol. Sci. 20:454.

    Not in our library10.3390/ijms20020454

  243. 243.

    Lin S. J. Defossez P. A. Guarente L. (2000 ). Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289 2126–2128.

    Not in our library10.1126/science.289.5487.2126

  244. 244.

    Liszczak G. Diehl K. L. Dann G. P. Muir T. W. (2018 ). Acetylation blocks DNA damage-induced chromatin ADP-ribosylation. Nat. Chem. Biol. 14 837–840.

    Not in our library10.1038/s41589-018-0097-1

  245. 245.

    Liu G. Bi Y. Shen B. Yang H. Zhang Y. Wang X. (2014 ). SIRT1 limits the function and fate of myeloid-derived suppressor cells in tumors by orchestrating HIF-1alpha-dependent glycolysis. Cancer Res. 74 727–737.

    Not in our library10.1158/0008-5472.can-13-2584

  246. 246.

    Liu P. Y. Xu N. Malyukova A. Scarlett C. J. Sun Y. T. Zhang X. D. (2013 ). The histone deacetylase SIRT2 stabilizes Myc oncoproteins. Cell Death Differ. 20 503–514.

    Not in our library10.1038/cdd.2012.147

  247. 247.

    Liu T. Tee A. E. Porro A. Smith S. A. Dwarte T. Liu P. Y. (2007 ). Activation of tissue transglutaminase transcription by histone deacetylase inhibition as a therapeutic approach for Myc oncogenesis. Proc. Natl. Acad. Sci. U.S.A. 104 18682–18687.

    Not in our library10.1073/pnas.0705524104

  248. 248.

    Liu X. Wang D. Zhao Y. Tu B. Zheng Z. Wang L. (2011 ). Methyltransferase Set7/9 regulates p53 activity by interacting with Sirtuin 1 (SIRT1). Proc. Natl. Acad. Sci. U.S.A. 108 1925–1930.

    Not in our library10.1073/pnas.1019619108

  249. 249.

    Liu Y. Peng L. Seto E. Huang S. Qiu Y. (2012 ). Modulation of histone deacetylase 6 (HDAC6) nuclear import and tubulin deacetylase activity through acetylation. J. Biol. Chem. 287 29168–29174.

    Not in our library10.1074/jbc.m112.371120

  250. 250.

    Lombard D. B. Alt F. W. Cheng H. L. Bunkenborg J. Streeper R. S. Mostoslavsky R. (2007 ). Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol. Cell. Biol. 27 8807–8814.

    Not in our library10.1128/mcb.01636-07

  251. 251.

    Lu J. Holmgren A. (2014 ). The thioredoxin antioxidant system. Free Radic. Biol. Med. 66 75–87.

    Not in our library10.1016/j.freeradbiomed.2013.07.036

  252. 252.

    Lu X. Tang M. Zhu Q. Yang Q. Li Z. Bao Y. (2019 ). GLP-catalyzed H4K16me1 promotes 53BP1 recruitment to permit DNA damage repair and cell survival. Nucleic Acids Res. 47 10977–10993.

    Not in our library10.1093/nar/gkz897

  253. 253.

    Lu X. F. Cao X. Y. Zhu Y. J. Wu Z. R. Zhuang X. Shao M. Y. (2018 ). Histone deacetylase 3 promotes liver regeneration and liver cancer cells proliferation through signal transducer and activator of transcription 3 signaling pathway. Cell Death Dis. 9:398.

    Not in our library10.1038/s41419-018-0428-x

  254. 254.

    Lu Y. Stuart J. H. Talbot-Cooper C. Agrawal-Singh S. Huntly B. Smid A. I. (2019 ). Histone deacetylase 4 promotes type I interferon signaling, restricts DNA viruses, and is degraded via vaccinia virus protein C6. Proc. Natl. Acad. Sci. U.S.A. 116 11997–12006.

    Not in our library10.1073/pnas.1816399116

  255. 255.

    Lu Y. F. Xu X. P. Lu X. P. Zhu Q. Liu G. Bao Y. T. (2020 ). SIRT7 activates p53 by enhancing PCAF-mediated MDM2 degradation to arrest the cell cycle. Oncogene 39 4650–4665.

    Not in our library10.1038/s41388-020-1305-5

  256. 256.

    Lu Z. Zou J. Li S. Topper M. J. Tao Y. Zhang H. (2020 ). Epigenetic therapy inhibits metastases by disrupting premetastatic niches. Nature 579 284–290.

    Not in our library10.1038/s41586-020-2054-x

  257. 257.

    Luger K. Mader A. W. Richmond R. K. Sargent D. F. Richmond T. J. (1997 ). Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389 251–260.

    Not in our library10.1038/38444

  258. 258.

    Luo J. Nikolaev A. Y. Imai S. Chen D. Su F. Shiloh A. (2001 ). Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107 137–148.

    Not in our library10.1016/s0092-8674(01)00524-4

  259. 259.

    Luo J. Su F. Chen D. Shiloh A. Gu W. (2000 ). Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 408 377–381.

    Not in our library10.1038/35042612

  260. 260.

    Mahalingam D. Mita M. Sarantopoulos J. Wood L. Amaravadi R. K. Davis L. E. (2014 ). Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy 10 1403–1414.

    Not in our library10.4161/auto.29231

  261. 261.

    Mani S. A. Guo W. Liao M. J. Eaton E. N. Ayyanan A. Zhou A. Y. (2008 ). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133 704–715.

    Not in our library10.1016/j.cell.2008.03.027

  262. 262.

    Mao R. Wu Y. Ming Y. Xu Y. Wang S. Chen X. (2019 ). Enhancer RNAs: a missing regulatory layer in gene transcription. Sci. China Life Sci. 62 905–912.

    Not in our library10.1007/s11427-017-9370-9

  263. 263.

    Mao Z. Hine C. Tian X. Van Meter M. Au M. Vaidya A. (2011 ). SIRT6 promotes DNA repair under stress by activating PARP1. Science 332 1443–1446.

    Not in our library10.1126/science.1202723

  264. 264.

    Marquardt J. U. Fischer K. Baus K. Kashyap A. Ma S. Krupp M. (2013 ). Sirtuin-6-dependent genetic and epigenetic alterations are associated with poor clinical outcome in hepatocellular carcinoma patients. Hepatology 58 1054–1064.

    Not in our library10.1002/hep.26413

  265. 265.

    Martin M. W. Lee J. Y. Lancia D. R. Jr. Ng P. Y. Han B. Thomason J. R. (2018 ). Discovery of novel N-hydroxy-2-arylisoindoline-4-carboxamides as potent and selective inhibitors of HDAC11. Bioorg. Med. Chem. Lett. 28 2143–2147.

    Not in our library10.1016/j.bmcl.2018.05.021

  266. 266.

    Mathias R. A. Greco T. M. Oberstein A. Budayeva H. G. Chakrabarti R. Rowland E. A. (2014 ). Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell 159 1615–1625.

    Not in our library10.1016/j.cell.2014.11.046

  267. 267.

    Mazur P. K. Herner A. Mello S. S. Wirth M. Hausmann S. Sanchez-Rivera F. J. (2015 ). Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat. Med. 21 1163–1171.

    Not in our library10.1038/nm.3952

  268. 268.

    Mckinsey T. A. Kuwahara K. Bezprozvannaya S. Olson E. N. (2006 ). Class II histone deacetylases confer signal responsiveness to the ankyrin-repeat proteins ANKRA2 and RFXANK. Mol. Biol. Cell 17 438–447.

    Not in our library10.1091/mbc.e05-07-0612

  269. 269.

    Mckinsey T. A. Zhang C. L. Lu J. Olson E. N. (2000 ). Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature 408 106–111.

    Not in our library10.1038/35040593

  270. 270.

    Mckinsey T. A. Zhang C. L. Olson E. N. (2001 ). Identification of a signal-responsive nuclear export sequence in class II histone deacetylases. Mol. Cell. Biol. 21 6312–6321.

    Not in our library10.1128/mcb.21.18.6312-6321.2001

  271. 271.

    Medina V. Edmonds B. Young G. P. James R. Appleton S. Zalewski P. D. (1997 ). Induction of caspase-3 protease activity and apoptosis by butyrate and trichostatin A (inhibitors of histone deacetylase): dependence on protein synthesis and synergy with a mitochondrial/cytochrome c-dependent pathway. Cancer Res. 57 3697–3707.

    Not in our library

  272. 272.

    Medon M. Vidacs E. Vervoort S. J. Li J. Jenkins M. R. Ramsbottom K. M. (2017 ). HDAC Inhibitor Panobinostat Engages Host Innate Immune Defenses to Promote the Tumoricidal Effects of Trastuzumab in HER2(+) Tumors. Cancer Res. 77 2594–2606.

    Not in our library10.1158/0008-5472.can-16-2247

  273. 273.

    Melo C. A. Drost J. Wijchers P. J. Van De Werken H. De Wit E. Oude Vrielink J. A. (2013 ). eRNAs are required for p53-dependent enhancer activity and gene transcription. Mol. Cell 49 524–535.

    Not in our library10.1016/j.molcel.2012.11.021

  274. 274.

    Meng F. Qian M. Peng B. Peng L. Wang X. Zheng K. (2020 ). Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiates the DNA damage response and repair in humans and mice. eLife 9:e55828.

    Not in our library10.7554/elife.55828

  275. 275.

    Michishita E. Park J. Y. Burneskis J. M. Barrett J. C. Horikawa I. (2005 ). Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol. Biol. Cell 16 4623–4635.

    Not in our library10.1091/mbc.e05-01-0033

  276. 276.

    Mihaylova M. M. Vasquez D. S. Ravnskjaer K. Denechaud P. D. Yu R. T. Alvarez J. G. (2011 ). Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 145 607–621.

    Not in our library10.1016/j.cell.2011.03.043

  277. 277.

    Millard C. J. Watson P. J. Celardo I. Gordiyenko Y. Cowley S. M. Robinson C. V. (2013 ). Class I HDACs share a common mechanism of regulation by inositol phosphates. Mol. Cell 51 57–67.

    Not in our library10.1016/j.molcel.2013.05.020

  278. 278.

    Miller K. M. Tjeertes J. V. Coates J. Legube G. Polo S. E. Britton S. (2010 ). Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining. Nat. Struct. Mol. Biol. 17 1144–1151.

    Not in our library10.1038/nsmb.1899

  279. 279.

    Ming M. Han W. Zhao B. Sundaresan N. R. Deng C. X. Gupta M. P. (2014 ). SIRT6 promotes COX-2 expression and acts as an oncogene in skin cancer. Cancer Res. 74 5925–5933.

    Not in our library10.1158/0008-5472.can-14-1308

  280. 280.

    Ming M. Shea C. R. Guo X. Li X. Soltani K. Han W. (2010 ). Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C. Proc. Natl. Acad. Sci. U.S.A. 107 22623–22628.

    Not in our library10.1073/pnas.1010377108

  281. 281.

    Mishra V. K. Wegwitz F. Kosinsky R. L. Sen M. Baumgartner R. Wulff T. (2017 ). Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4- and MYC-dependent manner. Nucleic Acids Res. 45 6334–6349.

    Not in our library10.1093/nar/gkx212

  282. 282.

    Miska E. A. Karlsson C. Langley E. Nielsen S. J. Pines J. Kouzarides T. (1999 ). HDAC4 deacetylase associates with and represses the MEF2 transcription factor. EMBO J. 18 5099–5107.

    Not in our library10.1093/emboj/18.18.5099

  283. 283.

    Mizushima N. (2018 ). A brief history of autophagy from cell biology to physiology and disease. Nat. Cell Biol. 20 521–527.

    Not in our library10.1038/s41556-018-0092-5

  284. 284.

    Mizushima N. Levine B. Cuervo A. M. Klionsky D. J. (2008 ). Autophagy fights disease through cellular self-digestion. Nature 451 1069–1075.

    Not in our library10.1038/nature06639

  285. 285.

    Mohrin M. Shin J. Liu Y. Brown K. Luo H. Xi Y. (2015 ). Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347 1374–1377.

    Not in our library10.1126/science.aaa2361

  286. 286.

    Monte M. Simonatto M. Peche L. Y. Bublik D. R. Gobessi S. Pierotti M. A. (2006 ). MAGE-A tumor antigens target p53 transactivation function through histone deacetylase recruitment and confer resistance to chemotherapeutic agents. Proc. Natl. Acad. Sci. U.S.A. 103 11160–11165.

    Not in our library10.1073/pnas.0510834103

  287. 287.

    Montgomery R. L. Davis C. A. Potthoff M. J. Haberland M. Fielitz J. Qi X. (2007 ). Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev. 21 1790–1802.

    Not in our library10.1101/gad.1563807

  288. 288.

    Montgomery R. L. Potthoff M. J. Haberland M. Qi X. Matsuzaki S. Humphries K. M. (2008 ). Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. J. Clin. Invest. 118 3588–3597.

    Not in our library10.1172/jci35847

  289. 289.

    Moon H. Zhu J. White A. C. (2019 ). Sirt5 is dispensable for Braf(V600E) -mediated cutaneous melanoma development and growth in vivo. Exp. Dermatol. 28 83–85.

    Not in our library10.1111/exd.13845

  290. 290.

    Moresi V. Carrer M. Grueter C. E. Rifki O. F. Shelton J. M. Richardson J. A. (2012 ). Histone deacetylases 1 and 2 regulate autophagy flux and skeletal muscle homeostasis in mice. Proc. Natl. Acad. Sci. U.S.A. 109 1649–1654.

    Not in our library10.1073/pnas.1121159109

  291. 291.

    Moresi V. Williams A. H. Meadows E. Flynn J. M. Potthoff M. J. Mcanally J. (2010 ). Myogenin and class II HDACs control neurogenic muscle atrophy by inducing E3 ubiquitin ligases. Cell 143 35–45.

    Not in our library10.1016/j.cell.2010.09.004

  292. 292.

    Musselman C. A. Lalonde M. E. Cote J. Kutateladze T. G. (2012 ). Perceiving the epigenetic landscape through histone readers. Nat. Struct. Mol. Biol. 19 1218–1227.

    Not in our library10.1038/nsmb.2436

  293. 293.

    Nagy L. Kao H. Y. Chakravarti D. Lin R. J. Hassig C. A. Ayer D. E. (1997 ). Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89 373–380.

    Not in our library10.1016/s0092-8674(00)80218-4

  294. 294.

    Nahalkova J. (2015 ). Novel protein-protein interactions of TPPII, p53, and SIRT7. Mol. Cell. Biochem. 409 13–22.

    Not in our library10.1007/s11010-015-2507-y

  295. 295.

    Naiman S. Huynh F. K. Gil R. Glick Y. Shahar Y. Touitou N. (2019 ). SIRT6 promotes hepatic beta-oxidation via activation of PPARalpha. Cell Rep. 29 4127–4143.e8.

    Not in our library10.1016/j.celrep.2019.11.067

  296. 296.

    Nakazawa M. S. Eisinger-Mathason T. S. Sadri N. Ochocki J. D. Gade T. P. Amin R. K. (2016 ). Epigenetic re-expression of HIF-2alpha suppresses soft tissue sarcoma growth. Nat. Commun. 7:10539.

    Not in our library10.1038/ncomms10539

  297. 297.

    Nan X. Ng H. H. Johnson C. A. Laherty C. D. Turner B. M. Eisenman R. N. (1998 ). Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393 386–389.

    Not in our library10.1038/30764

  298. 298.

    Nawrocki S. T. Carew J. S. Pino M. S. Highshaw R. A. Andtbacka R. H. Dunner K. (2006 ). Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res. 66 3773–3781.

    Not in our library10.1158/0008-5472.can-05-2961

  299. 299.

    Nebbioso A. Carafa V. Conte M. Tambaro F. P. Abbondanza C. Martens J. (2017 ). c-Myc Modulation and Acetylation Is a Key HDAC inhibitor target in cancer. Clin. Cancer Res. 23 2542–2555.

    Not in our library10.1158/1078-0432.ccr-15-2388

  300. 300.

    Newbold A. Salmon J. M. Martin B. P. Stanley K. Johnstone R. W. (2014 ). The role of p21(waf1/cip1) and p27(Kip1) in HDACi-mediated tumor cell death and cell cycle arrest in the Emu-myc model of B-cell lymphoma. Oncogene 33 5415–5423.

    Not in our library10.1038/onc.2013.482

  301. 301.

    Newkirk T. L. Bowers A. A. Williams R. M. (2009 ). Discovery, biological activity, synthesis and potential therapeutic utility of naturally occurring histone deacetylase inhibitors. Nat. Prod. Rep. 26 1293–1320.

    Not in our library10.1039/b817886k

  302. 302.

    Ng H. H. Zhang Y. Hendrich B. Johnson C. A. Turner B. M. Erdjument-Bromage H. (1999 ). MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat. Genet. 23 58–61.

    Not in our library10.1038/12659

  303. 303.

    Ng R. Huen M. S. Y. (2020 ). Deacetylation of a deacetylase drives the DNA damage response. Genome Instabil. Dis. 1 151–154.

    Not in our library10.1007/s42764-020-00018-7

  304. 304.

    Nguyen P. Lee S. Lorang-Leins D. Trepel J. Smart D. K. (2014 ). SIRT2 interacts with beta-catenin to inhibit Wnt signaling output in response to radiation-induced stress. Mol. Cancer Res. 12 1244–1253.

    Not in our library10.1158/1541-7786.mcr-14-0223-t

  305. 305.

    Nguyen P. Shukla S. Liu R. Abbineni G. Smart D. K. (2019 ). Sirt2 regulates radiation-induced injury. Radiat. Res. 191 398–412.

    Not in our library10.1667/rr15282.1

  306. 306.

    Nicholson J. Jevons S. J. Groselj B. Ellermann S. Konietzny R. Kerr M. (2017 ). E3 Ligase cIAP2 Mediates Downregulation of MRE11 and Radiosensitization in Response to HDAC Inhibition in Bladder Cancer. Cancer Res. 77 3027–3039.

    Not in our library10.1158/0008-5472.can-16-3232

  307. 307.

    Ning Y. Ding J. Sun X. Xie Y. Su M. Ma C. (2020 ). HDAC9 deficiency promotes tumor progression by decreasing the CD8(+) dendritic cell infiltration of the tumor microenvironment. J. Immunother. Cancer 8:e000529.

    Not in our library10.1136/jitc-2020-000529

  308. 308.

    Nishibuchi G. Shibata Y. Hayakawa T. Hayakawa N. Ohtani Y. Sinmyozu K. (2014 ). Physical and functional interactions between the histone H3K4 demethylase KDM5A and the nucleosome remodeling and deacetylase (NuRD) complex. J. Biol. Chem. 289 28956–28970.

    Not in our library10.1074/jbc.m114.573725

  309. 309.

    Nishimori S. Lai F. Shiraishi M. Kobayashi T. Kozhemyakina E. Yao T. P. (2019 ). PTHrP targets HDAC4 and HDAC5 to repress chondrocyte hypertrophy. JCI Insight 4:e97903.

    Not in our library10.1172/jci.insight.97903

  310. 310.

    Norsworthy K. J. Cho E. Arora J. Kowalski J. Tsai H. L. Warlick E. (2016 ). Differentiation therapy in poor risk myeloid malignancies: results of companion phase II studies. Leuk. Res. 49 90–97.

    Not in our library10.1016/j.leukres.2016.09.003

  311. 311.

    North B. J. Marshall B. L. Borra M. T. Denu J. M. Verdin E. (2003 ). The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol. Cell 11 437–444.

    Not in our library10.1016/s1097-2765(03)00038-8

  312. 312.

    Nott A. Watson P. M. Robinson J. D. Crepaldi L. Riccio A. (2008 ). S-Nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons. Nature 455 411–415.

    Not in our library10.1038/nature07238

  313. 313.

    Obayashi H. Nagano Y. Takahashi T. Seki T. Tanaka S. Sakai N. (2020 ). Histone deacetylase 10 knockout activates chaperone-mediated autophagy and accelerates the decomposition of its substrate. Biochem. Biophys. Res. Commun. 523 246–252.

    Not in our library10.1016/j.bbrc.2019.12.048

  314. 314.

    Oberdoerffer P. Michan S. Mcvay M. Mostoslavsky R. Vann J. Park S. K. (2008 ). SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135 907–918.

    Not in our library10.1016/j.cell.2008.10.025

  315. 315.

    Oberoi J. Fairall L. Watson P. J. Yang J. C. Czimmerer Z. Kampmann T. (2011 ). Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery. Nat. Struct. Mol. Biol. 18 177–184.

    Not in our library10.1038/nsmb.1983

  316. 316.

    Oehme I. Linke J. P. Bock B. C. Milde T. Lodrini M. Hartenstein B. (2013 ). Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc. Natl. Acad. Sci. U.S.A. 110 E2592–E2601.

    Not in our library10.1073/pnas.1300113110

  317. 317.

    Oki Y. Kelly K. R. Flinn I. Patel M. R. Gharavi R. Ma A. (2017 ). CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase I trial. Haematologica 102 1923–1930.

    Not in our library10.3324/haematol.2017.172882

  318. 318.

    Olsen E. A. Kim Y. H. Kuzel T. M. Pacheco T. R. Foss F. M. Parker S. (2007 ). Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J. Clin. Oncol. 25 3109–3115.

    Not in our library10.1200/jco.2006.10.2434

  319. 319.
    SIRT6 is a DNA double-strand break sensor · 2020
    No notice
  320. 320.

    Onyango P. Celic I. Mccaffery J. M. Boeke J. D. Feinberg A. P. (2002 ). SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. Proc. Natl. Acad. Sci. U.S.A. 99 13653–13658.

    Not in our library10.1073/pnas.222538099

  321. 321.

    Pal S. Kozono D. Yang X. Fendler W. Fitts W. Ni J. (2018 ). Dual HDAC and PI3K Inhibition Abrogates NFkappaB- and FOXM1-Mediated DNA Damage Response to Radiosensitize Pediatric High-Grade Gliomas. Cancer Res. 78 4007–4021.

    Not in our library10.1158/0008-5472.can-17-3691

  322. 322.

    Pan P. W. Feldman J. L. Devries M. K. Dong A. Edwards A. M. Denu J. M. (2011 ). Structure and biochemical functions of SIRT6. J. Biol. Chem. 286 14575–14587.

    Not in our library10.1074/jbc.m111.218990

  323. 323.

    Park I. Kwon M. S. Paik S. Kim H. Lee H. O. Choi E. (2017 ). HDAC2/3 binding and deacetylation of BubR1 initiates spindle assembly checkpoint silencing. FEBS J. 284 4035–4050.

    Not in our library10.1111/febs.14286

  324. 324.

    Park S. H. Ozden O. Liu G. Song H. Y. Zhu Y. Yan Y. (2016 ). SIRT2-mediated deacetylation and tetramerization of pyruvate kinase directs glycolysis and tumor growth. Cancer Res. 76 3802–3812.

    Not in our library10.1158/0008-5472.can-15-2498

  325. 325.

    Pei Y. Liu K. W. Wang J. Garancher A. Tao R. Esparza L. A. (2016 ). HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma. Cancer Cell 29 311–323.

    Not in our library10.1016/j.ccell.2016.02.011

  326. 326.

    Perez-Galan P. Roue G. Villamor N. Montserrat E. Campo E. Colomer D. (2006 ). The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood 107 257–264.

    Not in our library10.1182/blood-2005-05-2091

  327. 327.

    Phelps M. P. Bailey J. N. Vleeshouwer-Neumann T. Chen E. Y. (2016 ). CRISPR screen identifies the NCOR/HDAC3 complex as a major suppressor of differentiation in rhabdomyosarcoma. Proc. Natl. Acad. Sci. U.S.A. 113 15090–15095.

    Not in our library10.1073/pnas.1610270114

  328. 328.

    Pili R. Quinn D. I. Hammers H. J. Monk P. George S. Dorff T. B. (2017 ). Immunomodulation by entinostat in renal cell carcinoma patients receiving high-dose interleukin 2: a multicenter, single-Arm, Phase I/II Trial (NCI-CTEP#7870). Clin. Cancer Res. 23 7199–7208.

    Not in our library10.1158/1078-0432.ccr-17-1178

  329. 329.

    Pilie P. G. Tang C. Mills G. B. Yap T. A. (2019 ). State-of-the-art strategies for targeting the DNA damage response in cancer. Nat. Rev. Clin. Oncol. 16 81–104.

    Not in our library10.1038/s41571-018-0114-z

  330. 330.

    Popat R. Brown S. R. Flanagan L. Hall A. Gregory W. Kishore B. (2016 ). Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial. Lancet Haematol. 3 e572–e580.

    Not in our library10.1016/s2352-3026(16)30165-x

  331. 331.

    Potente M. Ghaeni L. Baldessari D. Mostoslavsky R. Rossig L. Dequiedt F. (2007 ). SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev. 21 2644–2658.

    Not in our library10.1101/gad.435107

  332. 332.

    Pouget J. P. Georgakilas A. G. Ravanat J. L. (2018 ). Targeted and off-target (bystander and abscopal) effects of radiation therapy: redox mechanisms and risk/benefit analysis. Antioxid. Redox Signal. 29 1447–1487.

    Not in our library10.1089/ars.2017.7267

  333. 333.

    Preglej T. Hamminger P. Luu M. Bulat T. Andersen L. Goschl L. (2020 ). Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation. JCI Insight 5:e133393.

    Not in our library10.1172/jci.insight.133393

  334. 334.

    Puvvada S. D. Guillen-Rodriguez J. M. Rivera X. I. Heard K. Inclan L. Schmelz M. (2017 ). A Phase II exploratory study of PXD-101 (Belinostat) followed by zevalin in patients with relapsed aggressive high-risk lymphoma. Oncology 93 401–405.

    Not in our library10.1159/000479230

  335. 335.

    Qi H. Shi X. Yu M. Liu B. Liu M. Song S. (2018 ). Sirtuin 7-mediated deacetylation of WD repeat domain 77 (WDR77) suppresses cancer cell growth by reducing WDR77/PRMT5 transmethylase complex activity. J. Biol. Chem. 293 17769–17779.

    Not in our library10.1074/jbc.ra118.003629

  336. 336.

    Qi J. Singh S. Hua W. K. Cai Q. Chao S. W. Li L. (2015 ). HDAC8 inhibition specifically targets Inv(16) acute myeloid leukemic stem cells by restoring p53 acetylation. Cell Stem Cell 17 597–610.

    Not in our library10.1016/j.stem.2015.08.004

  337. 337.

    Qian D. Z. Kachhap S. K. Collis S. J. Verheul H. M. Carducci M. A. Atadja P. (2006 ). Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha. Cancer Res. 66 8814–8821.

    Not in our library10.1158/0008-5472.can-05-4598

  338. 338.

    Radhakrishnan R. Li Y. Xiang S. Yuan F. Yuan Z. Telles E. (2015 ). Histone deacetylase 10 regulates DNA mismatch repair and may involve the deacetylation of MutS homolog 2. J. Biol. Chem. 290 22795–22804.

    Not in our library10.1074/jbc.m114.612945

  339. 339.

    Ramsey M. R. He L. Forster N. Ory B. Ellisen L. W. (2011 ). Physical association of HDAC1 and HDAC2 with p63 mediates transcriptional repression and tumor maintenance in squamous cell carcinoma. Cancer Res. 71 4373–4379.

    Not in our library10.1158/0008-5472.can-11-0046

  340. 340.

    Resh M. D. (2006 ). Trafficking and signaling by fatty-acylated and prenylated proteins. Nat. Chem. Biol. 2 584–590.

    Not in our library10.1038/nchembio834

  341. 341.

    Rezazadeh S. Yang D. Biashad S. A. Firsanov D. Takasugi M. Gilbert M. (2020 ). SIRT6 mono-ADP ribosylates KDM2A to locally increase H3K36me2 at DNA damage sites to inhibit transcription and promote repair. Aging 12 11165–11184.

    Not in our library10.18632/aging.103567

  342. 342.

    Rezazadeh S. Yang D. Tombline G. Simon M. Regan S. P. Seluanov A. (2019 ). SIRT6 promotes transcription of a subset of NRF2 targets by mono-ADP-ribosylating BAF170. Nucleic Acids Res. 47 7914–7928.

    Not in our library10.1093/nar/gkz528

  343. 343.

    Richon V. M. Sandhoff T. W. Rifkind R. A. Marks P. A. (2000 ). Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc. Natl. Acad. Sci. U.S.A. 97 10014–10019.

    Not in our library10.1073/pnas.180316197

  344. 344.

    Riggs M. G. Whittaker R. G. Neumann J. R. Ingram V. M. (1977 ). n-Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells. Nature 268 462–464.

    Not in our library10.1038/268462a0

  345. 345.

    Robert T. Vanoli F. Chiolo I. Shubassi G. Bernstein K. A. Rothstein R. (2011 ). HDACs link the DNA damage response, processing of double-strand breaks and autophagy. Nature 471 74–79.

    Not in our library10.1038/nature09803

  346. 346.

    Robertson K. D. Ait-Si-Ali S. Yokochi T. Wade P. A. Jones P. L. Wolffe A. P. (2000 ). DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat. Genet. 25 338–342.

    Not in our library10.1038/77124

  347. 347.

    Rodriguez-Gonzalez A. Lin T. Ikeda A. K. Simms-Waldrip T. Fu C. Sakamoto K. M. (2008 ). Role of the aggresome pathway in cancer: targeting histone deacetylase 6-dependent protein degradation. Cancer Res. 68 2557–2560.

    Not in our library10.1158/0008-5472.can-07-5989

  348. 348.

    Roos W. P. Thomas A. D. Kaina B. (2016 ). DNA damage and the balance between survival and death in cancer biology. Nat. Rev. Cancer 16 20–33.

    Not in our library10.1038/nrc.2015.2

  349. 349.

    Rountree M. R. Bachman K. E. Baylin S. B. (2000 ). DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat. Genet. 25 269–277.

    Not in our library10.1038/77023

  350. 350.
    Selective Sirt2 inhibition by ligand-induced rearrangement of the active site · 2015
    No notice
  351. 351.

    Rundlett S. E. Carmen A. A. Kobayashi R. Bavykin S. Turner B. M. Grunstein M. (1996 ). HDA1 and RPD3 are members of distinct yeast histone deacetylase complexes that regulate silencing and transcription. Proc. Natl. Acad. Sci. U.S.A. 93 14503–14508.

    Not in our library10.1073/pnas.93.25.14503

  352. 352.

    Ryu D. Jo Y. S. Lo Sasso G. Stein S. Zhang H. Perino A. (2014 ). A SIRT7-dependent acetylation switch of GABPbeta1 controls mitochondrial function. Cell Metab. 20 856–869.

    Not in our library10.1016/j.cmet.2014.08.001

  353. 353.

    Sanchez G. J. Richmond P. A. Bunker E. N. Karman S. S. Azofeifa J. Garnett A. T. (2018 ). Genome-wide dose-dependent inhibition of histone deacetylases studies reveal their roles in enhancer remodeling and suppression of oncogenic super-enhancers. Nucleic Acids Res. 46 1756–1776.

    Not in our library10.1093/nar/gkx1225

  354. 354.

    San-Miguel J. F. Hungria V. T. Yoon S. S. Beksac M. Dimopoulos M. A. Elghandour A. (2016 ). Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol. 3 e506–e515.

    Not in our library10.1016/s2352-3026(16)30147-8

  355. 355.
    SIRT6-dependent cysteine monoubiquitination in the PRE-SET domain of Suv39h1 regulates the NF-κB pathway · 2018
    Not checked
  356. 356.

    Scher M. B. Vaquero A. Reinberg D. (2007 ). SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress. Genes Dev. 21 920–928.

    Not in our library10.1101/gad.1527307

  357. 357.

    Schlicker C. Gertz M. Papatheodorou P. Kachholz B. Becker C. F. Steegborn C. (2008 ). Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J. Mol. Biol. 382 790–801.

    Not in our library10.1016/j.jmb.2008.07.048

  358. 358.

    Scholz C. Weinert B. T. Wagner S. A. Beli P. Miyake Y. Qi J. (2015 ). Acetylation site specificities of lysine deacetylase inhibitors in human cells. Nat. Biotechnol. 33 415–423.

    Not in our library10.1038/nbt.3130

  359. 359.

    Schreiber V. Dantzer F. Ame J. C. De Murcia G. (2006 ). Poly(ADP-ribose): novel functions for an old molecule. Nat. Rev. Mol. Cell Biol. 7 517–528.

    Not in our library10.1038/nrm1963

  360. 360.

    Schwer B. North B. J. Frye R. A. Ott M. Verdin E. (2002 ). The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J. Cell Biol. 158 647–657.

    Not in our library10.1083/jcb.200205057

  361. 361.

    Scully R. Panday A. Elango R. Willis N. A. (2019 ). DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat. Rev. Mol. Cell Biol. 20 698–714.

    Not in our library10.1038/s41580-019-0152-0

  362. 362.

    Sebastian C. Zwaans B. M. Silberman D. M. Gymrek M. Goren A. Zhong L. (2012 ). The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 151 1185–1199.

    Not in our library10.1016/j.cell.2012.10.047

  363. 363.

    Seigneurin-Berny D. Verdel A. Curtet S. Lemercier C. Garin J. Rousseaux S. (2001 ). Identification of components of the murine histone deacetylase 6 complex: link between acetylation and ubiquitination signaling pathways. Mol. Cell. Biol. 21 8035–8044.

    Not in our library10.1128/mcb.21.23.8035-8044.2001

  364. 364.

    Sen N. Kumari R. Singh M. I. Das S. (2013 ). HDAC5, a key component in temporal regulation of p53-mediated transactivation in response to genotoxic stress. Mol. Cell 52 406–420.

    Not in our library10.1016/j.molcel.2013.09.003

  365. 365.

    Senft D. Qi J. Ronai Z. A. (2018 ). Ubiquitin ligases in oncogenic transformation and cancer therapy. Nat. Rev. Cancer 18 69–88.

    Not in our library10.1038/nrc.2017.105

  366. 366.

    Serrano L. Martinez-Redondo P. Marazuela-Duque A. Vazquez B. N. Dooley S. J. Voigt P. (2013 ). The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation. Genes Dev. 27 639–653.

    Not in our library10.1101/gad.211342.112

  367. 367.

    Seto E. Yoshida M. (2014 ). Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol. 6:a018713.

    Not in our library10.1101/cshperspect.a018713

  368. 368.

    Shan B. Yao T. P. Nguyen H. T. Zhuo Y. Levy D. R. Klingsberg R. C. (2008 ). Requirement of HDAC6 for transforming growth factor-beta1-induced epithelial-mesenchymal transition. J. Biol. Chem. 283 21065–21073.

    Not in our library10.1074/jbc.m802786200

  369. 369.

    Shankaranarayana G. D. Motamedi M. R. Moazed D. Grewal S. I. (2003 ). Sir2 regulates histone H3 lysine 9 methylation and heterochromatin assembly in fission yeast. Curr. Biol. 13 1240–1246.

    Not in our library10.1016/s0960-9822(03)00489-5

  370. 370.

    Shaw E. Talwadekar M. Rashida Z. Mohan N. Acharya A. Khatri S. (2020 ). Anabolic SIRT4 exerts retrograde control over torc1 signaling by glutamine sparing in the mitochondria. Mol. Cell. Biol. 40:e00212-19.

    Not in our library10.1128/mcb.00212-19

  371. 371.

    Shechter D. Dormann H. L. Allis C. D. Hake S. B. (2007 ). Extraction, purification and analysis of histones. Nat. Protoc. 2 1445–1457.

    Not in our library10.1038/nprot.2007.202

  372. 372.
    PAX8 regulon in human ovarian cancer links lineage dependency with epigenetic vulnerability to HDAC inhibitors · 2019
    Not checked
  373. 373.

    Shi Y. Dong M. Hong X. Zhang W. Feng J. Zhu J. (2015 ). Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. Ann. Oncol. 26 1766–1771.

    Not in our library10.1093/annonc/mdv237

  374. 374.

    Shi Y. J. Matson C. Lan F. Iwase S. Baba T. Shi Y. (2005 ). Regulation of LSD1 histone demethylase activity by its associated factors. Mol. Cell 19 857–864.

    Not in our library10.1016/j.molcel.2005.08.027

  375. 375.

    Shinsky S. A. Christianson D. W. (2018 ). Polyamine deacetylase structure and catalysis: prokaryotic acetylpolyamine amidohydrolase and eukaryotic HDAC10. Biochemistry 57 3105–3114.

    Not in our library10.1021/acs.biochem.8b00079

  376. 376.

    Shogren-Knaak M. Ishii H. Sun J. M. Pazin M. J. Davie J. R. Peterson C. L. (2006 ). Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311 844–847.

    Not in our library10.1126/science.1124000

  377. 377.

    Simon M. Van Meter M. Ablaeva J. Ke Z. Gonzalez R. S. Taguchi T. (2019 ). LINE1 Derepression in Aged Wild-Type and SIRT6-deficient mice drives inflammation. Cell Metab. 29 871–885.e5.

    Not in our library10.1016/j.cmet.2019.02.014

  378. 378.

    Sinclair D. A. Guarente L. (2014 ). Small-molecule allosteric activators of sirtuins. Annu. Rev. Pharmacol. Toxicol. 54 363–380.

    Not in our library10.1146/annurev-pharmtox-010611-134657

  379. 379.
    Targeting Histone Deacetylases with Natural and Synthetic Agents: An Emerging Anticancer Strategy · 2018
    No notice
  380. 380.

    Singh R. Letai A. Sarosiek K. (2019 ). Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat. Rev. Mol. Cell Biol. 20 175–193.

    Not in our library10.1038/s41580-018-0089-8

  381. 381.

    Somoza J. R. Skene R. J. Katz B. A. Mol C. Ho J. D. Jennings A. J. (2004 ). Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure 12 1325–1334.

    Not in our library10.1016/j.str.2004.04.012

  382. 382.

    Son S. I. Cao J. Zhu C. L. Miller S. P. Lin H. (2019 ). Activity-Guided Design of HDAC11-Specific Inhibitors. ACS Chem. Biol. 14 1393–1397.

    Not in our library10.1021/acschembio.9b00292

  383. 383.

    Sparrow D. B. Miska E. A. Langley E. Reynaud-Deonauth S. Kotecha S. Towers N. (1999 ). MEF-2 function is modified by a novel co-repressor, MITR. EMBO J. 18 5085–5098.

    Not in our library10.1093/emboj/18.18.5085

  384. 384.

    Stojanovic N. Hassan Z. Wirth M. Wenzel P. Beyer M. Schafer C. (2017 ). HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer. Oncogene 36 1804–1815.

    Not in our library10.1038/onc.2016.344

  385. 385.

    Strahl B. D. Allis C. D. (2000 ). The language of covalent histone modifications. Nature 403 41–45.

    Not in our library10.1038/47412

  386. 386.

    Sun J. Piao J. Li N. Yang Y. Kim K. Y. Lin Z. (2020 ). Valproic acid targets HDAC1/2 and HDAC1/PTEN/Akt signalling to inhibit cell proliferation via the induction of autophagy in gastric cancer. FEBS J. 287 2118–2133.

    Not in our library10.1111/febs.15122

  387. 387.

    Sun L. Marin De Evsikova C. Bian K. Achille A. Telles E. Pei H. (2018 ). Programming and regulation of metabolic homeostasis by HDAC11. EBioMedicine 33 157–168.

    Not in our library10.1016/j.ebiom.2018.06.025

  388. 388.

    Sun Q. Y. Ding L. W. Johnson K. Zhou S. Tyner J. W. Yang H. (2019 ). SOX7 regulates MAPK/ERK-BIM mediated apoptosis in cancer cells. Oncogene 38 6196–6210.

    Not in our library10.1038/s41388-019-0865-8

  389. 389.

    Sun Y. Liu P. Y. Scarlett C. J. Malyukova A. Liu B. Marshall G. M. (2014 ). Histone deacetylase 5 blocks neuroblastoma cell differentiation by interacting with N-Myc. Oncogene 33 2987–2994.

    Not in our library10.1038/onc.2013.253

  390. 390.

    Sundaresan N. R. Samant S. A. Pillai V. B. Rajamohan S. B. Gupta M. P. (2008 ). SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol. Cell. Biol. 28 6384–6401.

    Not in our library10.1128/mcb.00426-08

  391. 391.

    Tae I. H. Park E. Y. Dey P. Son J. Y. Lee S. Y. Jung J. H. (2018 ). Novel SIRT1 inhibitor 15-deoxy-Delta12,14-prostaglandin J2 and its derivatives exhibit anticancer activity through apoptotic or autophagic cell death pathways in SKOV3 cells. Int. J. Oncol. 53 2518–2530.

    Not in our library10.3892/ijo.2018.4561

  392. 392.

    Tae I. H. Son J. Y. Lee S. H. Ahn M. Y. Yoon K. Yoon S. (2020 ). A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells. Int. J. Biol. Sci. 16 1901–1916.

    Not in our library10.7150/ijbs.44343

  393. 393.

    Tam W. L. Weinberg R. A. (2013 ). The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat. Med. 19 1438–1449.

    Not in our library10.1038/nm.3336

  394. 394.

    Tan M. Peng C. Anderson K. A. Chhoy P. Xie Z. Dai L. (2014 ). Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab. 19 605–617.

    Not in our library10.1016/j.cmet.2014.03.014

  395. 395.

    Tang M. Li Z. Zhang C. Lu X. Tu B. Cao Z. (2019 ). SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair. Sci. Adv. 5:eaav1118.

    Not in our library10.1126/sciadv.aav1118

  396. 396.

    Tang M. Lu X. Zhang C. Du C. Cao L. Hou T. (2017 ). Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer. Theranostics 7 1346–1359.

    Not in our library10.7150/thno.18804

  397. 397.

    Tang S. Fang Y. Huang G. Xu X. Padilla-Banks E. Fan W. (2017 ). Methionine metabolism is essential for SIRT1-regulated mouse embryonic stem cell maintenance and embryonic development. EMBO J. 36 3175–3193.

    Not in our library10.15252/embj.201796708

  398. 398.

    Tang S. Huang G. Fan W. Chen Y. Ward J. M. Xu X. (2014 ). SIRT1-mediated deacetylation of CRABPII regulates cellular retinoic acid signaling and modulates embryonic stem cell differentiation. Mol. Cell 55 843–855.

    Not in our library10.1016/j.molcel.2014.07.011

  399. 399.

    Tang X. Li G. Su F. Cai Y. Shi L. Meng Y. (2020 ). HDAC8 cooperates with SMAD3/4 complex to suppress SIRT7 and promote cell survival and migration. Nucleic Acids Res. 48 2912–2923.

    Not in our library10.1093/nar/gkaa039

  400. 400.
    SIRT7 antagonizes TGF-β signaling and inhibits breast cancer metastasis · 2017
    No notice
  401. 401.

    Tanno M. Sakamoto J. Miura T. Shimamoto K. Horio Y. (2007 ). Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J. Biol. Chem. 282 6823–6832.

    Not in our library10.1074/jbc.m609554200

  402. 402.

    Tanny J. C. Dowd G. J. Huang J. Hilz H. Moazed D. (1999 ). An enzymatic activity in the yeast Sir2 protein that is essential for gene silencing. Cell 99 735–745.

    Not in our library10.1016/s0092-8674(00)81671-2

  403. 403.

    Taunton J. Hassig C. A. Schreiber S. L. (1996 ). A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272 408–411.

    Not in our library10.1126/science.272.5260.408

  404. 404.

    Taverna S. D. Li H. Ruthenburg A. J. Allis C. D. Patel D. J. (2007 ). How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat. Struct. Mol. Biol. 14 1025–1040.

    Not in our library10.1038/nsmb1338

  405. 405.

    Tessarz P. Kouzarides T. (2014 ). Histone core modifications regulating nucleosome structure and dynamics. Nat. Rev. Mol. Cell Biol. 15 703–708.

    Not in our library10.1038/nrm3890

  406. 406.

    Tian J. L. Qin H. (2019 ). O-GlcNAcylation regulates primary ciliary length by promoting microtubule disassembly. iScience 12 379–391.

    Not in our library10.1016/j.isci.2019.01.031

  407. 407.

    Tian X. Firsanov D. Zhang Z. Cheng Y. Luo L. Tombline G. (2019 ). SIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species. Cell 177 622–638.e22.

    Not in our library10.1016/j.cell.2019.03.043

  408. 408.

    Tian Y. Wong V. W. Wong G. L. Yang W. Sun H. Shen J. (2015 ). Histone Deacetylase HDAC8 promotes insulin resistance and beta-catenin activation in NAFLD-associated hepatocellular carcinoma. Cancer Res. 75 4803–4816.

    Not in our library10.1158/0008-5472.can-14-3786

  409. 409.

    Toiber D. Erdel F. Bouazoune K. Silberman D. M. Zhong L. Mulligan P. (2013 ). SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling. Mol. Cell 51 454–468.

    Not in our library10.1016/j.molcel.2013.06.018

  410. 410.

    Tong J. Zheng X. Tan X. Fletcher R. Nikolovska-Coleska Z. Yu J. (2018 ). Mcl-1 phosphorylation without degradation mediates sensitivity to HDAC inhibitors by liberating BH3-only proteins. Cancer Res. 78 4704–4715.

    Not in our library10.1158/0008-5472.can-18-0399

  411. 411.

    Tong J. J. Liu J. Bertos N. R. Yang X. J. (2002 ). Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain. Nucleic Acids Res. 30 1114–1123.

    Not in our library10.1093/nar/30.5.1114

  412. 412.

    Topper M. J. Vaz M. Chiappinelli K. B. Destefano Shields C. E. Niknafs N. Yen R. C. (2017 ). Epigenetic therapy Ties MYC depletion to reversing immune evasion and treating lung cancer. Cell 171 1284–1300.e21.

    Not in our library10.1016/j.cell.2017.10.022

  413. 413.

    Toubai T. Tamaki H. Peltier D. C. Rossi C. Oravecz-Wilson K. Liu C. (2018 ). Mitochondrial Deacetylase SIRT3 plays an important role in donor T cell responses after experimental allogeneic hematopoietic transplantation. J. Immunol. 201 3443–3455.

    Not in our library10.4049/jimmunol.1800148

  414. 414.

    Tsuji N. Kobayashi M. Nagashima K. Wakisaka Y. Koizumi K. (1976 ). A new antifungal antibiotic, trichostatin. J. Antibiot. 29 1–6.

    Not in our library10.7164/antibiotics.29.1

  415. 415.
    The MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure · 2020
    Not checked
  416. 416.

    Ustinova K. Novakova Z. Saito M. Meleshin M. Mikesova J. Kutil Z. (2020 ). The disordered N-terminus of HDAC6 is a microtubule-binding domain critical for efficient tubulin deacetylation. J. Biol. Chem. 295 2614–2628.

    Not in our library10.1074/jbc.ra119.011243

  417. 417.

    Vakhrusheva O. Smolka C. Gajawada P. Kostin S. Boettger T. Kubin T. (2008 ). Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ. Res. 102 703–710.

    Not in our library10.1161/circresaha.107.164558

  418. 418.

    Van Den Wyngaert I. De Vries W. Kremer A. Neefs J. Verhasselt P. Luyten W. H. (2000 ). Cloning and characterization of human histone deacetylase 8. FEBS Lett. 478 77–83.

    Not in our library10.1016/s0014-5793(00)01813-5

  419. 419.

    Van Der Vlag J. Otte A. P. (1999 ). Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nat. Genet. 23 474–478.

    Not in our library10.1038/70602

  420. 420.

    Van Meter M. Kashyap M. Rezazadeh S. Geneva A. J. Morello T. D. Seluanov A. (2014 ). SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age. Nat. Commun. 5:5011.

    Not in our library10.1038/ncomms6011

  421. 421.

    Van Tilburg C. M. Milde T. Witt R. Ecker J. Hielscher T. Seitz A. (2019 ). Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia. Clin. Epigenetics 11:188.

    Not in our library10.1186/s13148-019-0775-1

  422. 422.

    Vaquero A. Scher M. Erdjument-Bromage H. Tempst P. Serrano L. Reinberg D. (2007 ). SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation. Nature 450 440–444.

    Not in our library10.1038/nature06268

  423. 423.

    Vaziri H. Dessain S. K. Ng Eaton E. Imai S. I. Frye R. A. Pandita T. K. (2001 ). hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107 149–159.

    Not in our library10.1016/s0092-8674(01)00527-x

  424. 424.

    Vazquez B. N. Thackray J. K. Simonet N. G. Chahar S. Kane-Goldsmith N. Newkirk S. J. (2019 ). SIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina. Nucleic Acids Res. 47 7870–7885.

    Not in our library10.1093/nar/gkz519

  425. 425.
    SIRT7 promotes genome integrity and modulates non‐homologous end joining DNA repair · 2016
    No notice
  426. 426.

    Verdel A. Curtet S. Brocard M. P. Rousseaux S. Lemercier C. Yoshida M. (2000 ). Active maintenance of mHDA2/mHDAC6 histone-deacetylase in the cytoplasm. Curr. Biol. 10 747–749.

    Not in our library10.1016/s0960-9822(00)00542-x

  427. 427.

    Verdin E. Ott M. (2015 ). 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. Nat. Rev. Mol. Cell Biol. 16 258–264.

    Not in our library10.1038/nrm3931

  428. 428.

    Vidali G. Boffa L. C. Bradbury E. M. Allfrey V. G. (1978 ). Butyrate suppression of histone deacetylation leads to accumulation of multiacetylated forms of histones H3 and H4 and increased DNase I sensitivity of the associated DNA sequences. Proc. Natl. Acad. Sci. U.S.A. 75 2239–2243.

    Not in our library10.1073/pnas.75.5.2239

  429. 429.

    Vogl D. T. Raje N. Jagannath S. Richardson P. Hari P. Orlowski R. (2017 ). Ricolinostat, the first selective histone deacetylase 6 inhibitor, in combination with bortezomib and dexamethasone for relapsed or refractory multiple myeloma. Clin. Cancer Res. 23 3307–3315.

    Not in our library10.1158/1078-0432.ccr-16-2526

  430. 430.

    Von Holt C. Brandt W. F. Greyling H. J. Lindsey G. G. Retief J. D. Rodrigues J. D. (1989 ). Isolation and characterization of histones. Methods Enzymol. 170 431–523.

    Not in our library10.1016/0076-6879(89)70061-6

  431. 431.

    Vriend J. Reiter R. J. (2016 ). Melatonin and the von Hippel-Lindau/HIF-1 oxygen sensing mechanism: a review. Biochim. Biophys. Acta 1865 176–183.

    Not in our library10.1016/j.bbcan.2016.02.004

  432. 432.

    Walkinshaw D. R. Weist R. Kim G. W. You L. Xiao L. Nie J. (2013 ). The tumor suppressor kinase LKB1 activates the downstream kinases SIK2 and SIK3 to stimulate nuclear export of class IIa histone deacetylases. J. Biol. Chem. 288 9345–9362.

    Not in our library10.1074/jbc.m113.456996

  433. 433.

    Wang A. Kurdistani S. K. Grunstein M. (2002 ). Requirement of Hos2 histone deacetylase for gene activity in yeast. Science 298 1412–1414.

    Not in our library10.1126/science.1077790

  434. 434.

    Wang A. H. Bertos N. R. Vezmar M. Pelletier N. Crosato M. Heng H. H. (1999 ). HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor. Mol. Cell. Biol. 19 7816–7827.

    Not in our library10.1128/mcb.19.11.7816

  435. 435.

    Wang A. H. Kruhlak M. J. Wu J. Bertos N. R. Vezmar M. Posner B. I. (2000 ). Regulation of histone deacetylase 4 by binding of 14-3-3 proteins. Mol. Cell. Biol. 20 6904–6912.

    Not in our library10.1128/mcb.20.18.6904-6912.2000

  436. 436.

    Wang A. H. Yang X. J. (2001 ). Histone deacetylase 4 possesses intrinsic nuclear import and export signals. Mol. Cell. Biol. 21 5992–6005.

    Not in our library10.1128/mcb.21.17.5992-6005.2001

  437. 437.

    Wang B. Rao Y. H. Inoue M. Hao R. Lai C. H. Chen D. (2014 ). Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production. Nat. Commun. 5:3479.

    Not in our library10.1038/ncomms4479

  438. 438.

    Wang B. Ye Y. Yang X. Liu B. Wang Z. Chen S. (2020 ). SIRT2-dependent IDH1 deacetylation inhibits colorectal cancer and liver metastases. EMBO Rep. 21:e48183.

    Not in our library10.15252/embr.201948183

  439. 439.

    Wang F. Nguyen M. Qin F. X. Tong Q. (2007 ). SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell 6 505–514.

    Not in our library10.1111/j.1474-9726.2007.00304.x

  440. 440.

    Wang H. Zhou W. Zheng Z. Zhang P. Tu B. He Q. (2012 ). The HDAC inhibitor depsipeptide transactivates the p53/p21 pathway by inducing DNA damage. DNA Repair 11 146–156.

    Not in our library10.1016/j.dnarep.2011.10.014

  441. 441.

    Wang J. Jiang J. Chen H. Wang L. Guo H. Yang L. (2019 ). FDA-approved drug screen identifies proteasome as a synthetic lethal target in MYC-driven neuroblastoma. Oncogene 38 6737–6751.

    Not in our library10.1038/s41388-019-0912-5

  442. 442.

    Wang R. H. Sengupta K. Li C. Kim H. S. Cao L. Xiao C. (2008 ). Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 14 312–323.

    Not in our library10.1016/j.ccr.2008.09.001

  443. 443.

    Wang W. W. Zeng Y. Wu B. Deiters A. Liu W. R. (2016 ). A chemical biology approach to reveal sirt6-targeted histone H3 sites in nucleosomes. ACS Chem. Biol. 11 1973–1981.

    Not in our library10.1021/acschembio.6b00243

  444. 444.

    Wang X. Waschke B. C. Woolaver R. A. Chen S. M. Y. Chen Z. Wang J. H. (2020 ). HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma. Protein Cell 11 472–482.

    Not in our library10.1007/s13238-020-00694-x

  445. 445.

    Wang Y. He J. Liao M. Hu M. Li W. Ouyang H. (2019 ). An overview of Sirtuins as potential therapeutic target: Structure, function and modulators. Eur. J. Med. Chem. 161 48–77.

    Not in our library10.1016/j.ejmech.2018.10.028

  446. 446.

    Wang Y. P. Zhou L. S. Zhao Y. Z. Wang S. W. Chen L. L. Liu L. X. (2014 ). Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress. EMBO J. 33 1304–1320.

    Not in our library10.1002/embj.201387224

  447. 447.

    Wang Z. Zang C. Cui K. Schones D. E. Barski A. Peng W. (2009 ). Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138 1019–1031.

    Not in our library10.1016/j.cell.2009.06.049

  448. 448.

    Watson P. J. Fairall L. Santos G. M. Schwabe J. W. (2012 ). Structure of HDAC3 bound to co-repressor and inositol tetraphosphate. Nature 481 335–340.

    Not in our library10.1038/nature10728

  449. 449.
    Insights into the activation mechanism of class I HDAC complexes by inositol phosphates · 2016
    No notice
  450. 450.

    Wei W. Liu X. Chen J. Gao S. Lu L. Zhang H. (2017 ). Class I histone deacetylases are major histone decrotonylases: evidence for critical and broad function of histone crotonylation in transcription. Cell Res. 27 898–915.

    Not in our library10.1038/cr.2017.68

  451. 451.
    Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis · 2018
    Corrected
  452. 452.

    Weinhouse S. (1956 ). On respiratory impairment in cancer cells. Science 124 267–269.

    Not in our library10.1126/science.124.3215.267

  453. 453.
    The histone deacetylase-3 complex contains nuclear receptor corepressors · 2000
    Not checked
  454. 454.

    Weng C. H. Chen L. Y. Lin Y. C. Shih J. Y. Lin Y. C. Tseng R. Y. (2019 ). Epithelial-mesenchymal transition (EMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI. Oncogene 38 455–468.

    Not in our library10.1038/s41388-018-0454-2

  455. 455.

    West A. C. Johnstone R. W. (2014 ). New and emerging HDAC inhibitors for cancer treatment. J. Clin. Invest. 124 30–39.

    Not in our library10.1172/jci69738

  456. 456.

    Wilson J. M. Le V. Q. Zimmerman C. Marmorstein R. Pillus L. (2006 ). Nuclear export modulates the cytoplasmic Sir2 homologue Hst2. EMBO Rep. 7 1247–1251.

    Not in our library10.1038/sj.embor.7400829

  457. 457.

    Winter M. Moser M. A. Meunier D. Fischer C. Machat G. Mattes K. (2013 ). Divergent roles of HDAC1 and HDAC2 in the regulation of epidermal development and tumorigenesis. EMBO J. 32 3176–3191.

    Not in our library10.1038/emboj.2013.243

  458. 458.

    Woods D. M. Woan K. V. Cheng F. Sodre A. L. Wang D. Wu Y. (2017 ). T cells lacking HDAC11 have increased effector functions and mediate enhanced alloreactivity in a murine model. Blood 130 146–155.

    Not in our library10.1182/blood-2016-08-731505

  459. 459.

    Wu L. P. Wang X. Li L. Zhao Y. Lu S. Yu Y. (2008 ). Histone deacetylase inhibitor depsipeptide activates silenced genes through decreasing both CpG and H3K9 methylation on the promoter. Mol. Cell. Biol. 28 3219–3235.

    Not in our library10.1128/mcb.01516-07

  460. 460.

    Wu M. Z. Tsai Y. P. Yang M. H. Huang C. H. Chang S. Y. Chang C. C. (2011 ). Interplay between HDAC3 and WDR5 is essential for hypoxia-induced epithelial-mesenchymal transition. Mol. Cell 43 811–822.

    Not in our library10.1016/j.molcel.2011.07.012

  461. 461.

    Xiao H. Jiao J. Wang L. O’brien S. Newick K. Wang L. C. (2016 ). HDAC5 controls the functions of Foxp3(+) T-regulatory and CD8(+) T cells. Int. J. Cancer 138 2477–2486.

    Not in our library10.1002/ijc.29979

  462. 462.

    Xu C. Jin J. Bian C. Lam R. Tian R. Weist R. (2012 ). Sequence-specific recognition of a PxLPxI/L motif by an ankyrin repeat tumbler lock. Sci. Signal. 5:ra39.

    Not in our library10.1126/scisignal.2002979

  463. 463.

    Xu L. Li Y. Zhou L. Dorfman R. G. Liu L. Cai R. (2019 ). SIRT3 elicited an anti-Warburg effect through HIF1alpha/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis. Cancer Med. 8 2380–2391.

    Not in our library10.1002/cam4.2089

  464. 464.

    Xu W. Ngo L. Perez G. Dokmanovic M. Marks P. A. (2006 ). Intrinsic apoptotic and thioredoxin pathways in human prostate cancer cell response to histone deacetylase inhibitor. Proc. Natl. Acad. Sci. U.S.A. 103 15540–15545.

    Not in our library10.1073/pnas.0607518103

  465. 465.

    Xu Y. Zhang S. Lin S. Guo Y. Deng W. Zhang Y. (2017 ). WERAM: a database of writers, erasers and readers of histone acetylation and methylation in eukaryotes. Nucleic Acids Res. 45 D264–D270.

    Not in our library10.1093/nar/gkw1011

  466. 466.

    Yan W. Liu S. Xu E. Zhang J. Zhang Y. Chen X. (2013 ). Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8. Oncogene 32 599–609.

    Not in our library10.1038/onc.2012.81

  467. 467.

    Yan W. W. Liang Y. L. Zhang Q. X. Wang D. Lei M. Z. Qu J. (2018 ). Arginine methylation of SIRT7 couples glucose sensing with mitochondria biogenesis. EMBO Rep. 19:e46377.

    Not in our library10.15252/embr.201846377

  468. 468.

    Yan Y. An J. Yang Y. Wu D. Bai Y. Cao W. (2018 ). Dual inhibition of AKT-mTOR and AR signaling by targeting HDAC3 in PTEN- or SPOP-mutated prostate cancer. EMBO Mol. Med. 10:e8478.

    Not in our library10.15252/emmm.201708478

  469. 469.

    Yang L. Ma X. He Y. Yuan C. Chen Q. Li G. (2017 ). Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors. Sci. China Life Sci. 60 249–256.

    Not in our library10.1007/s11427-016-0060-7

  470. 470.

    Yang W. Nagasawa K. Munch C. Xu Y. Satterstrom K. Jeong S. (2016 ). Mitochondrial sirtuin network reveals dynamic SIRT3-dependent deacetylation in response to membrane depolarization. Cell 167 985–1000.e21.

    Not in our library10.1016/j.cell.2016.10.016

  471. 471.

    Yang W. Xia Y. Hawke D. Li X. Liang J. Xing D. (2012 ). PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 150 685–696.

    Not in our library10.1016/j.cell.2012.07.018

  472. 472.

    Yang W. Xia Y. Ji H. Zheng Y. Liang J. Huang W. (2011 ). Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature 480 118–122.

    Not in our library10.1038/nature10598

  473. 473.

    Yang W. M. Inouye C. Zeng Y. Bearss D. Seto E. (1996 ). Transcriptional repression by YY1 is mediated by interaction with a mammalian homolog of the yeast global regulator RPD3. Proc. Natl. Acad. Sci. U.S.A. 93 12845–12850.

    Not in our library10.1073/pnas.93.23.12845

  474. 474.

    Yang W. M. Yao Y. L. Sun J. M. Davie J. R. Seto E. (1997 ). Isolation and characterization of cDNAs corresponding to an additional member of the human histone deacetylase gene family. J. Biol. Chem. 272 28001–28007.

    Not in our library10.1074/jbc.272.44.28001

  475. 475.

    Yang X. Wang Z. Li X. Liu B. Liu M. Liu L. (2018 ). SHMT2 desuccinylation by SIRT5 drives cancer cell proliferation. Cancer Res. 78 372–386.

    Not in our library10.1158/0008-5472.can-17-1912

  476. 476.

    Yang X. J. Gregoire S. (2005 ). Class II histone deacetylases: from sequence to function, regulation, and clinical implication. Mol. Cell. Biol. 25 2873–2884.

    Not in our library10.1128/mcb.25.8.2873-2884.2005

  477. 477.

    Yang X. J. Gregoire S. (2007 ). Metabolism, cytoskeleton and cellular signalling in the grip of protein Nepsilon - and O-acetylation. EMBO Rep. 8 556–562.

    Not in our library10.1038/sj.embor.7400977

  478. 478.

    Yang X. J. Seto E. (2008a ). Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol. Cell 31 449–461.

    Not in our library10.1016/j.molcel.2008.07.002

  479. 479.

    Yang X. J. Seto E. (2008b ). The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat. Rev. Mol. Cell Biol. 9 206–218.

    Not in our library10.1038/nrm2346

  480. 480.

    Yang Y. Tse A. K. Li P. Ma Q. Xiang S. Nicosia S. V. (2011 ). Inhibition of androgen receptor activity by histone deacetylase 4 through receptor SUMOylation. Oncogene 30 2207–2218.

    Not in our library10.1038/onc.2010.600

  481. 481.

    Yang Y. Zhao Y. Liao W. Yang J. Wu L. Zheng Z. (2009 ). Acetylation of FoxO1 activates Bim expression to induce apoptosis in response to histone deacetylase inhibitor depsipeptide treatment. Neoplasia 11 313–324.

    Not in our library10.1593/neo.81358

  482. 482.

    Yao Y. Yang Y. Zhu W. G. (2014 ). Sirtuins: nodes connecting aging, metabolism and tumorigenesis. Curr. Pharm. Des. 20 1614–1624.

    Not in our library10.2174/13816128113199990513

  483. 483.
    Sirtuin1 activator SRT2183 suppresses glioma cell growth involving activation of endoplasmic reticulum stress pathway · 2019
    Not checked
  484. 484.

    Ye X. Tam W. L. Shibue T. Kaygusuz Y. Reinhardt F. Ng Eaton E. (2015 ). Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature 525 256–260.

    Not in our library10.1038/nature14897

  485. 485.

    Yoshida M. Horinouchi S. (1999 ). Trichostatin and leptomycin. Inhibition of histone deacetylation and signal-dependent nuclear export. Ann. N. Y. Acad. Sci. 886 23–36.

    Not in our library10.1111/j.1749-6632.1999.tb09397.x

  486. 486.

    You A. Tong J. K. Grozinger C. M. Schreiber S. L. (2001 ). CoREST is an integral component of the CoREST- human histone deacetylase complex. Proc. Natl. Acad. Sci. U.S.A. 98 1454–1458.

    Not in our library10.1073/pnas.98.4.1454

  487. 487.

    Younes A. Berdeja J. G. Patel M. R. Flinn I. Gerecitano J. F. Neelapu S. S. (2016 ). Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. Lancet Oncol. 17 622–631.

    Not in our library10.1016/s1470-2045(15)00584-7

  488. 488.

    Yu M. Shi X. Ren M. Liu L. Qi H. Zhang C. (2020 ). SIRT7 deacetylates STRAP to regulate p53 activity and stability. Int. J. Mol. Sci. 21:4122.

    Not in our library10.3390/ijms21114122

  489. 489.

    Yuan H. Tan B. Gao S. J. (2017 ). Tenovin-6 impairs autophagy by inhibiting autophagic flux. Cell Death Dis. 8:e2608.

    Not in our library10.1038/cddis.2017.25

  490. 490.

    Yuan H. Wang Z. Li L. Zhang H. Modi H. Horne D. (2012 ). Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis. Blood 119 1904–1914.

    Not in our library10.1182/blood-2011-06-361691

  491. 491.

    Yuan J. Luo K. Liu T. Lou Z. (2012 ). Regulation of SIRT1 activity by genotoxic stress. Genes Dev. 26 791–796.

    Not in our library10.1101/gad.188482.112

  492. 492.

    Yuan Z. Zhang X. Sengupta N. Lane W. S. Seto E. (2007 ). SIRT1 regulates the function of the Nijmegen breakage syndrome protein. Mol. Cell 27 149–162.

    Not in our library10.1016/j.molcel.2007.05.029

  493. 493.

    Yue L. Sharma V. Horvat N. P. Akuffo A. A. Beatty M. S. Murdun C. (2020 ). HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms. Blood 135 191–207.

    Not in our library10.1182/blood.2019895326

  494. 494.

    Yun T. Yu K. Yang S. Cui Y. Wang Z. Ren H. (2016 ). Acetylation of p53 Protein at Lysine 120 Up-regulates Apaf-1 Protein and Sensitizes the Mitochondrial Apoptotic Pathway. J. Biol. Chem. 291 7386–7395.

    Not in our library10.1074/jbc.m115.706341

  495. 495.

    Zaware N. Zhou M. M. (2019 ). Bromodomain biology and drug discovery. Nat. Struct. Mol. Biol. 26 870–879.

    Not in our library10.1038/s41594-019-0309-8

  496. 496.

    Zhang C. L. Mckinsey T. A. Chang S. Antos C. L. Hill J. A. Olson E. N. (2002a ). Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110 479–488.

    Not in our library10.1016/s0092-8674(02)00861-9

  497. 497.

    Zhang C. L. Mckinsey T. A. Olson E. N. (2002b ). Association of class II histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation. Mol. Cell. Biol. 22 7302–7312.

    Not in our library10.1128/mcb.22.20.7302-7312.2002

  498. 498.

    Zhang D. Yoon H. G. Wong J. (2005 ). JMJD2A is a novel N-CoR-interacting protein and is involved in repression of the human transcription factor achaete scute-like homologue 2 (ASCL2/Hash2). Mol. Cell. Biol. 25 6404–6414.

    Not in our library10.1128/mcb.25.15.6404-6414.2005

  499. 499.

    Zhang M. Wu J. Sun R. Tao X. Wang X. Kang Q. (2019 ). SIRT5 deficiency suppresses mitochondrial ATP production and promotes AMPK activation in response to energy stress. PLoS One 14:e0211796.

    Not in our library10.1371/journal.pone.0211796

  500. 500.

    Zhang P. Tu B. Wang H. Cao Z. Tang M. Zhang C. (2014 ). Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion. Proc. Natl. Acad. Sci. U.S.A. 111 10684–10689.

    Not in our library10.1073/pnas.1411026111

  501. 501.

    Zhang P. Y. Li G. Deng Z. J. Liu L. Y. Chen L. Tang J. Z. (2016 ). Dicer interacts with SIRT7 and regulates H3K18 deacetylation in response to DNA damaging agents. Nucleic Acids Res. 44 3629–3642.

    Not in our library10.1093/nar/gkv1504

  502. 502.

    Zhang X. Chen X. Lin J. Lwin T. Wright G. Moscinski L. C. (2012a ). Myc represses miR-15a/miR-16-1 expression through recruitment of HDAC3 in mantle cell and other non-Hodgkin B-cell lymphomas. Oncogene 31 3002–3008.

    Not in our library10.1038/onc.2011.470

  503. 503.

    Zhang X. Zhao X. Fiskus W. Lin J. Lwin T. Rao R. (2012b ). Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas. Cancer Cell 22 506–523.

    Not in our library10.1016/j.ccr.2012.09.003

  504. 504.

    Zhang Y. Kwon S. Yamaguchi T. Cubizolles F. Rousseaux S. Kneissel M. (2008 ). Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol. Cell. Biol. 28 1688–1701.

    Not in our library10.1128/mcb.01154-06

  505. 505.

    Zhang Y. Ng H. H. Erdjument-Bromage H. Tempst P. Bird A. Reinberg D. (1999 ). Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13 1924–1935.

    Not in our library10.1101/gad.13.15.1924

  506. 506.

    Zhang Y. Wang X. L. Zhou M. Kang C. Lang H. D. Chen M. T. (2018 ). Crosstalk between gut microbiota and Sirtuin-3 in colonic inflammation and tumorigenesis. Exp. Mol. Med. 50:21.

    Not in our library10.1038/s12276-017-0002-0

  507. 507.

    Zhao K. Zhou Z. (2019 ). Post-translational modifications of nuclear sirtuins. Genome Instabil. Dis. 1 34–45.

    Not in our library10.1007/s42764-019-00001-x

  508. 508.

    Zhao W. Kruse J. P. Tang Y. Jung S. Y. Qin J. Gu W. (2008 ). Negative regulation of the deacetylase SIRT1 by DBC1. Nature 451 587–590.

    Not in our library10.1038/nature06515

  509. 509.

    Zhao X. Sternsdorf T. Bolger T. A. Evans R. M. Yao T. P. (2005 ). Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Mol. Cell. Biol. 25 8456–8464.

    Not in our library10.1128/mcb.25.19.8456-8464.2005

  510. 510.

    Zhao Y. Lu S. Wu L. Chai G. Wang H. Chen Y. (2006 ). Acetylation of p53 at lysine 373/382 by the histone deacetylase inhibitor depsipeptide induces expression of p21(Waf1/Cip1). Mol. Cell. Biol. 26 2782–2790.

    Not in our library10.1128/mcb.26.7.2782-2790.2006

  511. 511.

    Zhao Y. Yang J. Liao W. Liu X. Zhang H. Wang S. (2010 ). Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat. Cell Biol. 12 665–675.

    Not in our library10.1038/ncb2069

  512. 512.

    Zhong L. D’urso A. Toiber D. Sebastian C. Henry R. E. Vadysirisack D. D. (2010 ). The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140 280–293.

    Not in our library10.1016/j.cell.2009.12.041

  513. 513.

    Zhou L. Wang F. Sun R. Chen X. Zhang M. Xu Q. (2016 ). SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense. EMBO Rep. 17 811–822.

    Not in our library10.15252/embr.201541643

  514. 514.

    Zhou X. Marks P. A. Rifkind R. A. Richon V. M. (2001 ). Cloning and characterization of a histone deacetylase, HDAC9. Proc. Natl. Acad. Sci. U.S.A. 98 10572–10577.

    Not in our library10.1073/pnas.191375098

  515. 515.

    Zhu G. Tao T. Zhang D. Liu X. Qiu H. Han L. (2016 ). O-GlcNAcylation of histone deacetylases 1 in hepatocellular carcinoma promotes cancer progression. Glycobiology 26 820–833.

    Not in our library10.1093/glycob/cww025

  516. 516.

    Zhu W. G. (2017 ). Regulation of p53 acetylation. Sci. China Life Sci. 60 321–323.

    Not in our library10.1007/s11427-016-0353-0

  517. 517.

    Zhu W. G. Dai Z. Ding H. Srinivasan K. Hall J. Duan W. (2001a ). Increased expression of unmethylated CDKN2D by 5-aza-2’-deoxycytidine in human lung cancer cells. Oncogene 20 7787–7796.

    Not in our library10.1038/sj.onc.1204970

  518. 518.

    Zhu W. G. Lakshmanan R. R. Beal M. D. Otterson G. A. (2001b ). DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors. Cancer Res. 61 1327–1333.

    Not in our library

  519. 519.

    Zhu W. G. Srinivasan K. Dai Z. Duan W. Druhan L. J. Ding H. (2003 ). Methylation of adjacent CpG sites affects Sp1/Sp3 binding and activity in the p21(Cip1) promoter. Mol. Cell. Biol. 23 4056–4065.

    Not in our library10.1128/mcb.23.12.4056-4065.2003

  520. 520.

    Zou X. Zhu Y. Park S. H. Liu G. O’brien J. Jiang H. (2017 ). SIRT3-mediated dimerization of IDH2 directs cancer cell metab.olism and tumor growth. Cancer Res. 77 3990–3999.

    Not in our library10.1158/0008-5472.can-16-2393

  521. 521.

    Zullo K. M. Guo Y. Cooke L. Jirau-Serrano X. Mangone M. Scotto L. (2015 ). Aurora A kinase inhibition selectively synergizes with histone deacetylase inhibitor through cytokinesis failure in T-cell Lymphoma. Clin. Cancer Res. 21 4097–4109.

    Not in our library10.1158/1078-0432.ccr-15-0033

  522. 522.

    Zupkovitz G. Grausenburger R. Brunmeir R. Senese S. Tischler J. Jurkin J. (2010 ). The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation. Mol. Cell. Biol. 30 1171–1181.

    Not in our library10.1128/mcb.01500-09

Cited by papers we hold 6

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.