Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 25, 2026.

Deubiquitinases and the new therapeutic opportunities offered to cancer

Roland Pfoh, Ira Kay Lacdao, Vivian Saridakis

Endocrine-Related Cancer · 2015 · Review

doi:10.1530/erc-14-0516

Abstract

Deubiquitinases (DUBs) play important roles and therefore are potential drug targets in various diseases including cancer and neurodegeneration. In this review, we recapitulate structure–function studies of the most studied DUBs including USP7, USP22, CYLD, UCHL1, BAP1, A20, as well as ataxin 3 and connect them to regulatory mechanisms and their growing protein interaction networks. We then describe DUBs that have been associated with endocrine carcinogenesis with a focus on prostate, ovarian, and thyroid cancer, pheochromocytoma, and adrenocortical carcinoma. The goal is enhancing our understanding of the connection between dysregulated DUBs and cancer to permit the design of therapeutics and to establish biomarkers that could be used in diagnosis and prognosis.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 25, 2026. Paragraph numbers are ours, so an answer can point at one.

Ubiquitination

The ubiquitin–proteasome system (UPS) has many critical regulatory roles in eukaryotic cellular processes including cell cycle progression, stress response, signal transduction, transcriptional activation, and DNA repair. Malfunction, dysregulation, or molecular defects within the UPS lead to several different disease states including various cancers as well as neurodegenerative disorders. The UPS is responsible for the regulation, stability, and turnover of many different substrate proteins. However, the post-translational ubiquitination of a target protein has many other fates within eukaryotic cells as well.

Ubiquitin is a 76-residue eukaryotic polypeptide that is covalently attached to target proteins through an isopeptide bond formed between its terminal Gly residue and the ε-amino group of a lysine residue on the target protein. The ubiquitin superfamily of proteins possesses a similar three-dimensional structure, called the ββαββ fold or β-grasp fold, in the absence of sequence similarity. Proteins other than ubiquitin that possess this fold are called ubiquitin-like proteins and ubiquitin-like domains are found in many different proteins involved in the ubiquitination system. Ubiquitin is encoded by four different genes (UBB, UBC, UBA52, and UBA80 (RPS27A)) and is produced as a precursor that must be proteolytically processed to release mature ubiquitin. The ubiquitin amino acid sequence is much conserved between eukaryotic organisms with only two residue changes between the yeast and human proteins. A single ubiquitin moiety can be attached to substrate proteins resulting in mono-ubiquitination. Mono-ubiquitination is involved in a variety of cellular processing including protein translocation, kinase activation, epigenetic regulation, and DNA damage signaling. The N-terminal methionine and the seven lysine residues in ubiquitin (K6, K11, K27, K29, K33 K48, and K63) can form polyubiquitin chains. The attachment of a polyubiquitin chain to substrate proteins results in a variety of cellular effects. The best characterized is Lys48 (K48) polyubiquitination, which targets proteins for degradation by the 26S proteasome complex. Lys63 (K63) polyubiquitination plays important roles in DNA damage signaling and recruitment of DNA repair proteins to the site of damage. K63 and linear polyubiquitination function in the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling pathway. Ubiquitination plays many additional roles depending on the chain configuration and linkage. There is increasing evidence for the formation of more complex topologies with mixed linkages with unknown functions.

The attachment of ubiquitin to target proteins is mediated by an enzymatic cascade consisting of E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin-protein ligases) proteins (Fig. 1; ). E1 is the ubiquitin-activating enzyme that catalyzes the ATP-dependent activation of ubiquitin resulting in the formation of a thioester bond between the C-terminus of ubiquitin and a cysteine residue in the E1 active site. Activated ubiquitin is subsequently transferred to an E2 ubiquitin-conjugating enzyme and again forms a thioester bond between its C-terminus and a cysteine residue in the E2 active site. There are at least four different classes of E3 ubiquitin protein ligases whose function is to recognize and catalyze the ubiquitination of the substrate protein. The first class of E3 ubiquitin protein ligases contains a Really Interesting New Gene (RING) domain and acts as a scaffold between the ubiquitin-conjugated E2 and the target protein to be ubiquitinated. The RING domain-containing protein is essential for target protein recognition and mediates the transfer of the ubiquitin from the E2 onto the target protein. Another class of E3 ligases contains a homologous to the E6-AP carboxyl terminus (HECT) domain. Unlike RING domain proteins, HECT domain proteins actually catalyze the transfer of ubiquitin from the loaded E2 onto a cysteine residue in their active site forming a thioester bond and then finally onto the substrate protein. The third class is called U-box, whose members function like RING E3 ligases and have a RING-like fold; however, they lack the cysteine and histidine Zn-coordination sites. The latest identified class of E3 ligases is the RING-inbetween-RING (RBR) family, which are hybrid RING/HECT type E3 ligases containing three variant RING domains, known as RING1, IBR/BRcat, and RING2/Rcat. Similar to HECT proteins, they catalyze the transfer of ubiquitin to a cysteine in the active site of the RING2/Rcat domain. The RING1 domain mediates interactions with the E2 enzyme. The specificity and type of ubiquitination is generated from substrate recognition by the E3 and the formation of different E2–E3 complex combinations that mediate ubiquitination.

Deubiquitination

Protein ubiquitination is both dynamic and reversible. Deubiquitinases or deubiquitinating enzymes (DUBs) catalyze the removal of ubiquitin from target proteins and are also involved in ubiquitin maturation, recycling, and editing (Fig. 2;,,,, ). Processes that can be regulated by deubiquitination include the rescue of proteins that are destined for degradation, the cleavage to release mature ubiquitin, the editing of a polyubiquitin on a substrate protein as well as the removal of ubiquitin to terminate or alter a biological event. DUBs are associated with the 26S proteasome to rescue ubiquitin chains before the degradation of the substrate protein. These unanchored polyubiquitin chains are then processed by other DUBs to replenish the free ubiquitin pool in the cell. DUBs are divided into two main classes according to their enzymatic cleavage mechanism: cysteine proteases and zinc metalloproteases. The larger group of cysteine proteases is further divided into four classes according to sequence conservation in the catalytic domain. Currently, the five known DUB families include ubiquitin C-terminal hydrolases (UCHs), ubiquitin-specific proteases (USPs), Machado–Joseph disease (MJD) protein domain proteases, ovarian tumor proteases (OTUs), and JAMM motif zinc metalloproteases. There are ∼90 human DUBs; however, the biological roles and target proteins are unknown for many of them. The importance of DUBs in cellular functions as well as carcinogenesis has been recently reviewed. By far, USPs are the largest class of DUBs with ∼60 proteases in humans, their sizes ranging from ∼50–300 kDa and most of them containing several domains in addition to the catalytic domain. Sequence conservation among these proteases is limited to the catalytic domain, which is characterized by an active site catalytic triad containing Cys, His, and Asp (or Asn) residues. As the non-catalytic domains are highly diverse at the amino acid sequence level, it is hypothesized that they are important for conferring substrate specificity, regulation of the catalytic activity, and mediating protein interactions to the individual USPs. UCHs were the first identified family of DUBs with four members in humans. The role of UCHs was initially proposed to be in the salvage and maturation of ubiquitin, as they are unable to cleave long polyubiquitin chains. The remaining families of DUBs, OTU, Josephin, and JAMM are described later in this review. DUB specificity and regulation are currently being investigated. With so many DUBs, it is easy to imagine that each DUB will have different modes of regulation and substrates. Most importantly, the majority of DUBs are found in protein complexes, whereby specificity and regulation can be controlled. Other DUBs are activated by post-translational modifications including phosphorylation, sumoylation, and ubiquitination. Some DUBs are specific for their target substrates and some DUBs are also specific for the ubiquitin chain type (K48 vs K63 linked). Most DUBs specifically recognize ubiquitin and cannot catalyze the proteolysis of ubiquitin-like proteins. DUBs also have specificity that determines where proteolysis occurs with some DUBs cleaving from the end of a polyubiquitin chain, whereas others cleave internally.

Deubiquitinases

All DUBs that play important roles in pathways that are dysregulated in cancer including DNA repair, cell growth, and apoptosis are potential drug targets. However, the difficulty in development of effective drugs may be the challenge in designing specific inhibitors for a single DUB. This challenge is similar to that encountered in the design of inhibitors against protein kinases that have hampered drug development for many years. However, there are currently several potent kinase inhibitor drugs in the market, indicating that these concerns are indeed valid and challenging but certainly not insurmountable. The three-dimensional structures of the catalytic domains of USP2, USP7, USP8, and USP14 have revealed striking structural conservation of their active site, thus substantiating the concerns that drug development may be difficult. Interestingly, these crystal structures also revealed that these catalytic domains were in inactive conformations before ubiquitin binding, suggesting alternative targets for drug design. As the binding of ubiquitin activates USPs, it is desirable to identify compounds that bind to the catalytic domains and prevent the binding of ubiquitin. However, in parallel to targeting the catalytic domains of USPs for drug design, it would be advantageous to target individual substrate recognition, regulatory or protein interaction domains, as this would avoid concerns about cross-reactivity. Each USP has at least one or more of these domains and there is no sequence or structure conservation between most USP domains making these attractive drug-interaction sites. The ability to prevent complex formation between USPs and their ubiquitinated substrates is desirable for the design of drug compounds that interfere with specific deubiquitination processes. Therefore, structural analysis to reveal the molecular mechanism of interaction between USPs and their substrates will greatly enhance the development of these inhibitors. However, directly targeting large protein–protein interaction surfaces is quite challenging and requires precise structural knowledge of the interaction sites. The ability to understand the pathways and proteins that are involved in key regulatory events leading to disease will allow the development of therapeutics that targets only these proteins.

The structure–function relationships of selected DUBs will be discussed in the following section. We chose at least one example from each of the five DUB classes (USP-class: USP7, CYLD, and USP22; OTU-class: A20; UCH-class: UCHL1 and BRCA1-associated protein 1 (BAP1); MJD-class: ataxin 3 (ATXN3); and JAMM-class: Rpn11). Within their classes, the DUBS were selected based on the number of publications, disease relevance, as well as the available data on structure–function relationships. Overall, USP7, CYLD, UCHL1, BAP1, A20, and ATXN3 are the most intensively studied DUBS based on the number of citations in PubMed. All of the selected DUBS are related to cancer.

Ubiquitin-specific protease 7

USP7 was initially identified through its interaction with the ICP0 protein of herpes simplex virus. Subsequently, USP7 was also shown to interact with the EBNA1 protein from Epstein–Barr virus, vIRF4 and LANA proteins from Kaposi's sarcoma herpesvirus, UL35 from cytomegalovirus, and E1B-55K from adenovirus. Therefore, USP7 has emerged as a common target of herpesviruses (and perhaps other DNA viruses) living up to its original name of herpesvirus-associated USP (HAUSP).

USP7 regulates the turnover of many critical proteins involved in tumor suppression and DNA repair. p53, a tumor suppressor that induces cell cycle arrest and apoptosis, was the first protein to be identified as a USP7 substrate. Apart from p53, USP7 also deubiquitinates and stabilizes Hdm2 and HdmX, which are negative regulators of p53, indicating a complex regulatory mechanism. Hdm2 is preferentially targeted by USP7 over p53 under normal unstressed conditions; however, USP7 targets p53 in response to DNA damage. It has recently been shown that both GMPS and Abro1 modulate USP7-mediated deubiquitination of p53 after DNA damage. The deletion of the USP7 gene resulted in early embryonic lethality partly due to increased p53 levels. USP7 regulates the localization, rather than the stability, of tumor suppressors phosphatase and tensin homolog (PTEN) and FOXO4 by deubiquitinating their monoubiquitinated, transcriptionally active, nuclear forms. USP7 also plays important roles in genomic stability by deubiquitinating and stabilizing many proteins involved in these pathways including BUB3, claspin, ARF-BP1, and others. These USP7 substrate proteins play critical roles in pathways that are often dysregulated in cancer highlighting the importance of investigating USP7 as a therapeutic target in cancers involving these proteins.

GMPS is not only involved in nucleotide biosynthesis but also modulates the function of USP7 deubiquitination of both H2B and p53, resulting in epigenetic silencing and DNA repair respectively. The role of USP7 in epigenetic silencing is not limited to H2B deubiquitination, as it also deubiquitinates and stabilizes RING1B, BMI1, UHRF1, and DNMT1, proteins that are involved in chromatin remodeling and epigenetic regulation.

Individual USP7 domains have been structurally characterized, including the catalytic domain with bound ubiquitin-aldehyde, the TNF receptor-associated factor (TRAF)-like N-terminal domain (USP7-NTD) with various peptides from different substrates (p53, Hdm2, HdmX, and UbE2E1) as well as the five ubiquitin-like domains of the C-terminus (Fig. 3). USP7-NTD is a protein–protein interaction domain involved primarily in substrate recognition, whereas USP7-CTD is involved in protein–protein interactions and regulation of catalytic activity.

The ability to understand how and when USP7 deubiquitinates each substrate is essential to our overall understanding of its function. Owing to its regulation of Hdm2, HdmX, and p53, USP7 is an exemplary USP drug target. In cancers that are caused by a dysregulated Hdm2 protein but retain WT p53, the ability to inhibit USP7 deubiquitination of Hdm2 is considered to be of therapeutic importance because Hdm2 degradation would lead to p53 stabilization and activation. Therefore, a drug that prevents the formation of the Hdm2/USP7 complex or inhibits its catalytic activity will benefit patients with cancer associated with a dysregulated Hdm2 protein. Elevated levels of USP7 have been recently discovered in prostate cancer and glioma. USP7 was also implicated to modulate tumor growth and apoptosis in a colon carcinoma xenograft model. As well, reduced expression of USP7 was observed in non-small cell lung carcinomas. The recent discoveries of new USP7 substrates (such as Rb and BMI) implicate its possible involvement in other cancers indicating a need for USP7 therapeutics.

Several USP7 inhibitors have been tested in a variety of in vitro and in vivo assays. HBX 41,108 and P5091 are USP7 inhibitors with IC50 values of submicromolar concentrations. The potency of HBX 41,108 has been studied in HCT116, human colon carcinoma cells, where it was shown to inhibit cell growth and induce apoptosis. The potency of P5091 was shown to induce apoptosis in multiple myeloma cells resistant to bortezomib. However, to date, there have not been any studies evaluating USP7 inhibitors in endocrine-related cancers.

CYLD

Similar to USP7, CYLD belongs to the USP class of cysteine proteases (Fig. 3). Together with A20 (see below), CYLD regulates the pathway of NFκB, which is a key regulatory protein in the response of the immune system to infections. Dysregulation of the NFκB pathway is involved not only in cancer, but also in a number of other diseases such as viral infection and inflammatory diseases. It has been recently suggested that CYLD down-regulation could increase breast cancer metastasis through NFκB activation. The USP domain of CYLD is located at the C-terminus and contains a zinc-binding B-box domain. Though similar to the RING finger, the zinc-binding domain does not show E3 ligase activity and does not alter enzymatic activity or substrate specificity, but is relevant for the localization of CYLD to the cytoplasm. Compared with other USP domains (e.g. USP7), the USP finger region involved in ubiquitin binding is shorter, which could explain the preference of CYLD for K63-linked ubiquitin chains. In addition to the USP domain, CYLD contains three cytoskeleton-associated protein-glycine-conserved (CAP-Gly) domains. Its three-dimensional fold is similar to the SH domain, which is a binding motif for proline-rich sequences. CYLD negatively regulates the NFκB pathway by deubiquitinating critical factors such as NFκB essential modulator (NEMO, also called IKKγ) and TRAF2.

Ubiquitin-specific protease 22

USP22 consists of 525 amino acids and contains an N-terminal UBP-type zinc finger and a C-terminal USP domain. It is involved in the deubiquitination of NAD-dependent protein deacetylase sirtuin 1 (SIRT1; ), as well as histones H2A and H2B, as part of the transcriptional regulatory histone acetylation and deubiquitination complex known as Spt-Ada-Gcn5 acetyltransferase (SAGA). Structural data on USP22 are not available, but its yeast ortholog Ubp8 (ubiquitin processing protease 8) has been crystallized within the deubiquitination module of the SAGA complex. The SAGA DUB module is a tight complex between Ubp8, Sgf11, Sgf73, and Sus1, and Ubp8 is allosterically regulated by its binding partners. USP22 is involved in oncogenesis due to its role in a large variety of cancers. USP22 expression is increased in laryngeal squamous cell carcinoma, salivary adenoid cystic carcinoma, cervical cancer, salivary duct carcinoma, colorectal carcinoma, breast cancer, oral squamous cell carcinoma, and papillary carcinoma. The overexpression of USP22 is related to poor prognosis and may be used as a biomarker during diagnosis. USP22 has been identified as a cancer stem cell marker in the ‘death-from-cancer’ signature genes study. Genome-wide expression-profiling analysis identified 11 genes that could be used as markers to predict both metastases and failure of cancer treatment.

A20

By far, the most intensely studied member of the OTU-class of cysteine proteases is A20 (alternative name TNFAIP3: tumor necrosis factor alpha-induced protein); together with CYLD, it negatively regulates the NFκB pathway (Fig. 3). A20 is regulated by estrogen and A20 levels are highly increased in aggressive forms of breast cancer and involved in tamoxifen resistance, suggesting a potential role both as a marker and as a therapeutic target. However, A20 levels are decreased in B-cell lymphomas, leading to NFκB activation and contributing to their resistance to apoptosis. Unlike most other DUBs, A20 also possesses an E3 ubiquitin ligase function. This dual E3 ligase–DUB function allows A20 to elegantly inhibit NFκB-related signaling by removing K63-linked polyubiquitin chains from substrate molecules such as TRAF6 and receptor-interacting serine/threonine protein kinase 1 (RIP1) and label them for 26S proteasomal degradation by attaching a K48-linked polyubiquitin chain. A20 is generated in response to NFκB-induced gene activation and is thus part of the negative feedback mechanism in the NFκB pathway. For distinct functions in the NFκB pathway, A20 requires other proteins such as tax1-binding protein 1 (TAX1BP1), E3 ubiquitin-protein ligase Itchy homolog (ITCH), and RING finger protein 11 (RNF11) to form an A20 ubiquitin-editing complex. The C-terminus of A20 contains seven zinc finger (ZnF) domains, of which ZnF4 is essential for E3 ligase activity. Furthermore, this domain binds ubiquitin and TAX1BP1. The ZnF1 domain is essential for recognition of RIP1. ZnF4 has been crystallized with mono-ubiquitin and shows a high affinity for K63-linked polyubiquitin chains, whereas ZnF7 crystallized with linear di-ubiquitin. A comparison between the crystal structures of the N-terminal OTU-domain and otubain 2 (OTUB2) revealed different structural features around the catalytic triad, suggesting differences in substrate specificity as well as catalytic activity of the individual DUBs. Although the core architecture of the catalytic triad was found to be very similar in the USP- and OTU-domains, A20 showed variations in the third catalytic residue. A more recent crystallographic study has reported reversible oxidation of the catalytic cysteine residue in A20 and other OTU–DUBs, which is stabilized by the specific nature of the catalytic center and has been suggested as a regulatory mechanism.

UCHL1 (PGP 9.5)

UCHL1 (also known as PGP 9.5) is the most studied member of the UCH-class of cysteine protease DUBs and is associated with multiple types of cancers including lung, colorectal, pancreatic, and breast cancers as well as neurodegenerative diseases such as Parkinson's and Alzheimer's (Fig. 3). It is a marker for neuroendocrine cells and tumors and has been suggested as a detection tool for pancreatic, parathyroid, ovarian, and breast cancers. UCHL1 cleaves single amino acids or small peptides from the C-terminus of ubiquitin precursors to create mono-ubiquitin, but does not cleave ubiquitin from proteins. Dimeric UCHL1 displays E3 ubiquitin ligase activity in vitro. With only 223 amino acids, it is among the shortest DUBs, containing only a UCH domain. UCHL1 adopts a papain-like α–β–α fold similar to UCHL3 and UCHL5. The crystal structure of apo-UCHL1 showed a distorted catalytic triad, whereas with bound ubiquitin vinyl methyl ester the catalytic triad realigns into an active form. A similar scenario is present in USP7, where the catalytic triad was only properly aligned with bound ubiquitin-aldehyde. A tripeptide fluoromethylketone inhibitor has been shown to bind at the active site to the misaligned UCHL1 form. The precise physiological role of UCHL1 is somewhat elusive. In healthy subjects, it is exclusively expressed in the neurons and testis, but it is found in cancerous tissues. Mutations in UCHL1 have been linked to Parkinson's disease. Both protein and mRNA levels of UCHL1 are down-regulated in prostate cancer due to hypo-methylation of the UCHL1 promoter.

BRCA1-associated protein 1

Research into BAP1 has gained attention due to its role in lung and breast cancers and tumor suppression (Fig. 3). An extensive study found mutations and deletions to BAP1 to be particularly associated with the detrimental outcome of various common cancers, especially in renal clear cell carcinoma. BAP1 is named according to its interaction with the RING finger domain of BRCA1, which is an ubiquitin E3 ligase involved in DNA repair. Although BRCA1 itself is not a substrate of BAP1, its function is affected by BAP1. A recent study has linked the deubiquitination of γ-tubulin by BAP1 to breast cancer. Drosophila BAP1 has been found to form the so-called polycomb repressive DUB (PR-DUB) complex with the polycomb group (PcG) protein ASX (additional sex combs protein), which deubiquitinates mono-ubiquitinated histone H2A. The corresponding PR-DUB complex in humans involves BAP1 and host cell factor 1 (HCFC1). It had been observed earlier that HCFC1 is a substrate of BAP1, suggesting that BAP1 regulates cell proliferation. A recent study has found that the transcription factor forkhead box protein K2 (FOXK2) guides the PR-DUB complex to its targets on the genome via BAP1 binding. There is no structural information for BAP1. In addition to its UCH domain, BAP1 contains a long C-terminal extension. The C-terminal extension contains a functional nuclear core localization (NLS) domain and several binding sites for interaction partners such as BRCA1 and HCFC1. For tumor suppression, both the enzymatic activity and the NLS domain are essential.

Ataxin 3

ATXN3 belongs to the MJD class of cysteine proteases and is named after spinocerebellar ataxia type 3, a neurodegenerative disease, which is also called MJD (Fig. 3). A recent study has reported that ATXN3 represses the transcription of PTEN, an immensely important tumor suppressor critically linked to endocrine-related cancers. The regulation of PTEN by ATXN3 highlights an earlier study that suggested involvement of ATXN3 in gene expression by binding to specific DNA sequences as well as histone deacetylase 3 (HDAC3) and nuclear receptor corepressor (NCoR). In addition to the N-terminal catalytic Josephin domain, ATXN3 contains two C-terminal ubiquitin-interaction motifs (UIMs), which are also found in the 26S proteasome. ATXN3 shows preferred binding and cleavage of longer poly-ubiquitin, with a minimal chain length of four. Neighboring the two UIMs is a poly-glutamine (polyQ) stretch. ATXN3 mutations with extended polyQ stretches cause MJD. Ironically, normal ATXN3 is involved in the regulation of protein aggregates and supposedly plays a role in the suppression of polyQ-related neurodegenerative diseases such as Huntington's disease. Critical for this suppressive function are the UIM domains, the catalytic activity as well as proteasome activity. It has been suggested that the deubiquitinating function of ATXN3 protects against its own intrinsic polyQ toxicity. Binding of ATXN3 to valosin-containing protein (VCP, also called p97) suggested a regulatory involvement of ATXN3 in endoplasmatic reticulum-associated degradation, which is a quality control system targeting misfolded proteins for proteasomal digestion. ATXN3 regulates C-terminus of Hsc70-interacting protein, which is an E3 ligase that collaborates with chaperones in protein quality control. The catalytic Josephin domain of ATXN3 investigated by solution NMR revealed structural similarity to the catalytic domains of other cysteine proteases and ubiquitin binding.

Rpn11

Rpn11 (also known as PSMD14 or POH1) is an essential enzyme of the 26S proteasome and belongs to the 19S regulatory particle non-ATPase (Rpn) subunits (Fig. 3). Rpn11 is located in the lid of the proteasome in a hetero-dimeric complex with Rpn8. It cleaves K48-linked ubiquitin chains from proteasome substrates, which is necessary for proteasomal processing and degradation. Only recently, the involvement of the proteasome in DNA repair has been reported. In this respect, Rpn11 has been found to promote the double-strand DNA break response by restricting K63-linked ubiquitin chains attached to histones near damaged DNA sites. It had been observed earlier that Rpn11 can specifically cleave K63-linked poly-ubiquitin chains, which is contrary to its cleavage of K48-linked chains targeted for proteasomal digestion, but fits to the K63 specificity of other zinc metalloproteases such as AMSH (associated molecule with the SH3 domain of signal transducting adapter molecule 1) and AMSH-LP (AMSH-like protein). Rpn11 has also been connected to drug resistance in cancer as well as idiopathic nephrotic syndrome, which is a common kidney disease in children. Rpn11 alone is not active, and in complex with Rpn8 it displays low activity, suggesting that it is only fully functional when embedded into the 26S proteasome.

Endocrine cancers

The remainder of this review focuses on DUBs that have already been implicated in endocrine cancers.

Prostate cancer

Prostate cancer is the second most common cancer diagnosed and the second most common cause of cancer death in men worldwide. In the USA, an estimated 233 000 new cases of prostate cancer were predicted to be diagnosed in 2014 and ∼30 000 associated deaths. Prostate cancer is more frequently diagnosed in men over the age of 65. Screening for prostate cancer is based on the prostate-specific antigen blood test; however, abnormal levels require prostate biopsies for definitive diagnosis as well as digital rectal examination. Combinations of tumor surveillance, surgery, radiation, hormonal, and chemotherapies are used in the management and treatment of prostate cancer. The molecular basis of disease is quite complex and mutations in many different oncogenes and tumor suppressor genes have been implicated including TP53, RB1, EZH2, BMI, and PTEN. All of these genes have also been implicated in most other cancers; therefore, none are directly linked to prostate cancer alone. In light of all of the identified mutations, prostate cancer appears to be caused by dysregulation of many different cellular signaling pathways especially those involved in cell survival and apoptosis.

Interestingly, the DUB USP7 has been implicated in the regulation of several of these genes including TP53, RB1, BMI, and PTEN. The involvement of overexpressed USP7 has already been described in prostate cancer via dysregulation of PTEN. PTEN is a lipid and protein phosphatase that catalyzes the dephosphorylation of phosphatidylinositol (3,4,5)-triphosphate inhibiting the Akt/PKB signaling pathway. However, PTEN also has nuclear functions, whereby it regulates chromatin and DNA repair processes. It has recently become clear that in many cancers, PTEN is excluded from the nucleus. The ubiquitination of PTEN is one mechanism that leads to its nuclear translocation. In the nucleus, USP7 catalyzes the deubiquitination of PTEN leading to its export from the nucleus. This USP7-dependent deubiquitination and removal of PTEN from the nucleus is associated with many cancers. More recently, the ability of USP7 to deubiquitinate PTEN was found to be under the control of BCR-ABL. BCR-ABL phosphorylates USP7 and activates the deubiquitination of PTEN. A USP7 inhibitor could target prostate cancers; however, the effectiveness of such an inhibitor needs further study. Single nucleotide polymorphisms in Hdm2, HdmX, and USP7 have also been associated with aggressive prostate cancer. The involvement of USP7 in other mechanisms of prostate cancer awaits further investigations.

USP2a (also known as USP2) has been implicated in prostate cancer through its deubiquitination and stabilization of fatty acid synthase and more recently Hdm2 as well as its closely related functional homolog HdmX. Furthermore, overexpressed USP2a can transform prostate epithelial cells in vitro and NIH3T3 cells overexpressing USP2a caused the growth of tumors in all 12 injected nude mice in vivo. More importantly, USP2a was found to be overexpressed in prostate cancer and is regulated by androgens in a concentration-dependent manner. The inactivation of USP2a via knockdown, mutations, or low expression has a negative effect on fatty acid synthase levels and p53-regulated genes, which enhances apoptosis. USP2a levels were found to be up-regulated along with fatty acid synthase-related genes in almost half of all prostate cancers. These studies suggested an important role for USP2a in prostate cancer. It is therefore expected that an USP2a inhibitor could have important therapeutic applications. The c-myc oncogene is overexpressed in a subset of USP2a overexpressing prostate cancer cells. The stabilization of Hdm2 by USP2a results in enhanced degradation of p53, thus preventing apoptosis. This enhanced p53 degradation has a direct consequence in MYC up-regulation by repressing the expression of regulatory microRNAs that target the MYC mRNA. The derepression of microRNAs miR-34b/c, miR-98, and let-7c resulting in increased levels of MYC is attributed to increased levels of USP2a. Inhibitors targeting the catalytic activity of USP2a could attack prostate cancer cells via several different mechanisms, such as i) reducing MYC levels, thus reducing proliferation and ii) increasing p53 levels leading to increased apoptosis.

USP19 silencing directly affected the growth of several prostate cancer cell lines, suggesting a putative role in carcinogenesis. USP19 deubiquitinates and stabilizes KPC1, an E3 ligase for p27. Interestingly, the effects of decreased nuclear levels of p27, resulting in poor prognosis, have already been described in prostate cancer. USP19 regulates the levels of p27, although p27 is not a USP19 substrate.

One of the functions of USP26 is to regulate the activity and stability of the androgen receptor in the nucleus. The androgen receptor is a steroid hormone receptor that is responsible for male development and maturation. It is activated by binding androgens such as testosterone or dihydrotestosterone and is transported to the nucleus where it functions as a transcription factor. The androgen receptor has been implicated in several cancers including testicular, prostate, breast, and thyroid cancers. Investigation of the effects of USP26 in prostate cancer is necessary given its role in activity and stability of the androgen receptor and the role of the androgen receptor in prostate cancer. Similar to USP26, USP12 catalyzes the deubiquitination and stabilization of the androgen receptor. Furthermore, the functional role of USP12 in the increased transcriptional activation of the androgen receptor has been extended to the Akt pathway through the pro-apoptotic phosphatases (PHLPP and PHLPPL). The USP12/Uaf-1/WDR20 deubiquitinating complex also stabilizes both PHLPP and PHLPPL eventually resulting in increased transcriptional activation by the androgen receptor. Even though the role of USP10 in prostate cancer has not been investigated, it is interesting to note that USP10 is also involved in the regulation of the androgen receptor.

Betulinic acid, derived from the bark of white birch trees, induces apoptosis quite selectively in a variety of cancer cells. Betulinic acid had already been described to inhibit prostate cancer growth though a mechanism of action involving the decreased levels of VEGF and survivin due to the increased ubiquitin-mediated degradation of specificity protein transcription factors (Sp1, Sp3, and Sp4; ). Another study determined that betulinic acid increases the levels of poly-ubiquitinated proteins and their degradation and concluded that betulinic acid most probably inhibits the actions of several as yet unidentified DUBs.

Ovarian cancer

In the USA, an estimated 22 000 new cases of ovarian cancer were predicted to be diagnosed in 2014 resulting in ∼14 000 deaths associated with this disease. Ovarian cancer is asymptomatic until later stages making it quite difficult to diagnose. The number of deaths is quite high because of the late stages of disease and metastases. The greatest risk factor for ovarian cancer is genetic with several common mutations. The current understanding of the involvement of DUBs in ovarian cancer is rather limited. Many tumor suppressor genes including TP53, PTEN, RB1, and BRCA1 are either mutated or dysregulated in ovarian cancer. Therefore, as USP7 regulates all of these proteins, the role of USP7 in ovarian cancer needs to be investigated. The ubiquitin carboxyl terminal hydrolases UCH37 (also known as UCHL5) and UCHL1 have both been implicated in ovarian cancer. As in other cancers, UCH37 has been found to be up-regulated and linked to poor prognosis. UCHL1 has been identified as being both up-regulated and down-regulated in ovarian cancer. UCHL1 knockdown in ovarian cancer cell lines where it was overexpressed caused increased proliferation. Another study that set out to identify both up- and down-regulated genes in ovarian cancer for use in diagnosis determined that USP36 was overexpressed. More importantly, USP36 was identified in sera of 36% of cases from ovarian cancer patients compared with none from healthy subjects. Further investigations are needed to define the role of USP36 in ovarian and other cancers and confirm its ability to be useful in diagnosis. USP15 is amplified in ovarian and breast cancers as well as glioblastoma. USP15 regulates the TGFβ and NFκB signaling pathways by deubiquitinating the type 1 TGFβ receptor as well as IκBα. Proteins from both of these pathways have already been implicated as possible cancer therapeutic targets. Down-regulation of USP15 has been observed in paclitaxel-resistant ovarian cancer. Furthermore, knockdown of USP15 in HeLa cells also lead to paclitaxel resistance corroborating its important role in this resistance. Krüppel-like factor 8 (KLF8) is a transcription factor that is highly overexpressed in ovarian and other cancers. KLF8 can transform ovarian epithelial cells alone and in combination with other oncogenes by down-regulating USP44. USP44 plays a role in cancer through its dysregulation of the DNA damage response mediated by the E3 ligase RNF168 on histone H2A. USP44 is a tumor suppressor protein that is silenced in a variety of other cancers.

Pheochromocytoma

Pheochromocytoma is a usually benign cancer originating in the adrenal glands that is associated with Von Hippel–Lindau disease, neurofibromatosis, and multiple endocrine neoplasia type 2 and characterized by excessive secretion of catecholamines. Von Hippel–Landau disease is associated with various other malignancies as well. The following discussion continues only with Von Hippel–Landau disease, as it is related to the ubiquitin system. Von Hippel–Lindau disease is caused by mutations in the gene encoding the VHL protein (pVHL). The VHL protein associates with elongin B, elongin C, and cullin 2 to form an E3 ligase complex that is responsible for the regulation of hypoxia inducible factor 1 alpha (HIF1α). Under normoxia, pVHL catalyzes the poly-ubiquitination and degradation of HIF1α by interacting with a 2-hydroxylated proline on HIF1α. However, under conditions of hypoxia, HIF1α is not hydroxylated, therefore pVHL is unable to interact and catalyze its poly-ubiquitination. As a transcription factor, HIF1α induces expression of genes containing hypoxia response elements that are involved in angiogenesis, glucose metabolism, and invasion/metastasis. Mutations in pVHL disrupt the ubiquitination of HIF1α. Dysregulated degradation of HIF1α results in enhanced expression of its target genes. Two DUBs, VDU1 and VDU2 (pVHL-interacting deubiquitinating enzymes 1 and 2), are also known substrates of the pVHL E3 ligase complex. VDU1 is also known as USP33 and VDU2 as USP20. Both of these DUBs share sequence and functional similarities and are ubiquitinated by the pVHL–E3 ligase complex and targeted for degradation. In addition, VDU2, but not VDU1, is able to interact with and deubiquitinate HIF1α, and rescue it from proteasome-mediated degradation. Interestingly, pVHL regulates the levels of both HIF1α and VDU2 leading to a vital equilibrium between the degradation and rescue of HIF1α. The inability of the pVHL–E3 ligase complex to catalyze the ubiquitination of not only HIF1α but also VDU1 and VDU2 may lead to disease. As DUBs are substrates of the pVHL–E3 ligase complex, it is important to note that both of these DUBs are emerging targets in the development of therapeutics against Von Hippel–Landau disease. The design of inhibitors against VDU1 and VDU2 could prevent non-regulated deubiquitination of substrate proteins to compensate for the inability of the pVHL–E3 ligase complex to degrade it. USP20 is involved in the deubiquitination and rescue of RAD17, a protein involved in the DNA damage response pathway. The knockdown of USP20 caused the sensitization of two different cancer cell lines to cisplatin, strongly suggesting that an inhibitor against USP20 may function as a cancer therapeutic drug.

Thyroid cancer

In the USA, an estimated 63 000 new cases of thyroid cancer were predicted to be diagnosed in 2014 resulting in ∼1800 deaths. USP22 is overexpressed in papillary carcinoma, a type of thyroid cancer. Increased USP22 protein levels were shown for papillary carcinoma tissue when compared with noncancerous tissue using immunohistochemistry. Kaplan–Meier analysis indicated that the survival of patients with papillary carcinoma was significantly lower with high USP22 expression levels. Taken together, the authors concluded that USP22 could be functioning as an oncogene and used in the prognosis of papillary carcinoma. There is one case of MALT lymphoma of the thyroid that has been associated with the deletion of A20. The expression of OTUD1 is highly up-regulated in various carcinomas of the thyroid and could potentially be used as a biomarker to distinguish between cancerous samples.

UCHL1 belongs to the ubiquitin-carboxyl terminal hydrolases family of DUBs. This family of proteases catalyzes the hydrolysis of ubiquitin from small adducts to maintain cellular ubiquitin homeostasis. It is the main DUB responsible for maintaining cellular levels of monomeric ubiquitin primarily by hydrolyzing ester and amide forms of ubiquitin. It is highly expressed in neuronal and endocrine cells; however, its expression has been detected in many non-neuronal cancers. The role of UCHL1 in endocrine cancers is well established. The up-regulation of UCHL1 has been observed in one of the six cases of granular cell tumors located in the thyroid gland. UCHL1 is also known as PGP9.5, a well-established marker for diagnosis and prognosis of a variety of cancers. PGP9.5 was evaluated as a prognostic marker in invasive colorectal, pancreatic, parathyroid, and lung cancers. Patients with pancreatic cancer that were positive for PGP9.5 had lower survival rates than those who were negative for PGP9.5. There were significant differences in maximal tumor size and the extent of tumor in patients with invasive colorectal cancer expressing PGP9.5. PGP9.5 was evaluated as a diagnostic marker in medullary thyroid carcinoma. Overexpression of PGP9.5 mRNA was identified in all eleven medullary thyroid carcinoma samples examined. This study showed that levels of PGP9.5 mRNA were similar to normal thyroid tissues in other thyroid cancers including anaplastic, papillary, and follicular carcinomas as well as follicular adenoma, suggesting that overexpression of PGP9.5 could not be used as a biomarker for these cancers.

Both VDU1 (USP33) and VDU2 (USP20) also play important biological roles related to the thyroid. VDU1 and VDU2 deubiquitinate and thus reactivate the hormone-activating type 2 deiodinase (D2), which is an endoplasmic reticulum integral membrane protein. D2 functions in the conversion of the inactive precursor thyroxine, into triiodothyroxine (T3), the active hormone responsible for cellular energy and metabolism homeostasis. Therefore, very tight control of D2 levels is critical. The mechanism by which levels of T3 are controlled involves the ubiquitination leading to inactivation and the subsequent degradation of D2. D2 is ubiquitinated by the WSB-1 and TEB4 E3 ligases in response to D2 activation and increased levels of T3. However, the process of D2 degradation can be reversed by VDU1- and VDU2-catalyzed deubiquitination, resulting in D2 rescue and reactivation. It is unknown whether the deubiquitination of D2 has any roles in VHL disease or cancer.

Adrenocortical carcinoma

Adrenocortical adenoma and carcinoma are tumors of the adrenal cortex. Adrenocortical carcinoma is a rare but very aggressive cancer with a 5-year survival rate of 30%. Adenomas on the other hand are benign tumors. The up-regulation of USP4 and USP38 was identified in adrenocortical carcinoma using microarray gene expression analysis. USP4 had previously been identified as being up-regulated in adrenocortical carcinoma using transcriptional profiling. Several USP4 deubiquitinating targets have been identified including ARF-BP1, type 1 TGFβ receptor, and PDK1. The roles of ARF-BP1 and PDK1 in adrenocortical carcinomas have not yet been investigated. The TGF signaling pathway has been implicated in the tumorigenicity of adrenocortical carcinomas.

Therapeutic targeting of DUBs for the treatment of cancer

The studies thus far describing the involvement of DUBs in endocrine cancers have only scratched the surface of the many roles that DUBs may play in these cancers (Table 1). Additional studies are needed to define the actual landscape of DUBs that are mutated, deleted, or differentially regulated in these cancers. These studies, along with the design of targeted, small molecule DUB inhibitors, will most probably lead to new opportunities for endocrine cancer therapeutics and diagnostics.

DUBs have been implicated in several types of cancers and neurodegenerative diseases. As such, targeting DUBs can lead to effective therapies in the treatment, diagnosis, and prevention of these diseases. The UPS regulates many important proteins; therefore, it is not surprising that, when UPS components are acting aberrantly, accelerated degradation or mislocalization of substrate proteins results in disease. Various studies have suggested the dual roles of DUBs, both as oncogenes and as tumor suppressors. With DUBs having multiple substrates, the nature of their substrates may distinguish their oncogenic vs suppressive roles.

Velcade (bortezomib) was the first clinically approved UPS inhibitor and is used as a therapeutic agent for B cell lymphoma and multiple myeloma, exemplifying the importance of the UPS as an effective therapeutic target. Kyprolis (carfilzomib), another proteasome inhibitor, was FDA approved in 2012 for multiple myeloma. The biggest challenge in therapeutics is that a proteasome inhibitor is non-specific and indeed bortezomib and carfilzomib treatments are quite toxic. A potentially more attractive therapeutic approach would be inhibitors designed with increased specificity against DUBs.

Concluding remarks

A more comprehensive understanding of the roles, substrates, and regulation of DUBs will lead to a better understanding of their emerging roles in carcinogenesis and clinical applications of their inhibitors. The continued and accelerated development of small molecule inhibitors against DUBs will lead to increased success in the treatment of various cancers and other diseases.

References 218

  1. 1.

    Alimonti A, Carracedo A, Clohessy JG, Trotman LC, Nardella C, Egia A, Salmena L, Sampieri K, Haveman WJ, Brogi E, et al. Subtle variations in Pten dose determine cancer susceptibility. Nature Genetics. 2010;42:454-458.

    Not in our library10.1038/ng.556

  2. 2.

    Allende-Vega N, Sparks A, Lane DP, Saville MK. MdmX is a substrate for the deubiquitinating enzyme USP2a. Oncogene. 2010;29:432-441.

    Not in our library10.1038/onc.2009.330

  3. 3.

    Amerik AY, Hochstrasser M. Mechanism and function of deubiquitinating enzymes. Biochimica et Biophysica Acta. 2004;1695:189-207.

    Not in our library10.1016/j.bbamcr.2004.10.003

  4. 4.

    Aravind L, Koonin EV. The U box is a modified RING finger – a common domain in ubiquitination. Current Biology. 2000;10:R132-R134.

    Not in our library10.1016/s0960-9822(00)00398-5

  5. 5.

    Avvakumov GV, Walker JR, Xue S, Finerty PJ, Mackenzie F, Newman EM, Dhe-Paganon S. Amino-terminal dimerization, NRDP1–rhodanese interaction, and inhibited catalytic domain conformation of the ubiquitin-specific protease 8 (USP8). Journal of Biological Chemistry. 2006;281:38061-38070.

    Not in our library10.1074/jbc.m606704200

  6. 6.

    Becker K, Marchenko ND, Palacios G, Moll UM. A role of HAUSP in tumor suppression in a human colon carcinoma xenograft model. Cell Cycle. 2008;7:1205-1213.

    Not in our library10.4161/cc.7.9.5756

  7. 7.

    Ben-Aroya S, Agmon N, Yuen K, Kwok T, McManus K, Kupiec M, Hieter P. Proteasome nuclear activity affects chromosome stability by controlling the turnover of Mms22, a protein important for DNA repair. PLoS Genetics. 2010;6:e1000852.

    Not in our library10.1371/journal.pgen.1000852

  8. 8.

    Benassi B, Flavin R, Marchionni L, Zanata S, Pan Y, Chowdhury D, Marani M, Strano S, Muti P, Blandino G, et al. MYC is activated by USP2a-mediated modulation of microRNAs in prostate cancer. Cancer Discovery. 2012;2:236-247.

    Not in our library10.1158/2159-8290.cd-11-0219

  9. 9.

    Bhattacharya S, Ghosh MK. Cell death and deubiquitinases: perspectives in cancer. BioMed Research International. 2014a;2014:435197.

    Not in our library10.1155/2014/435197

  10. 10.

    Bhattacharya S, Ghosh MK. HAUSP, a novel deubiquitinase for Rb – MDM2 the critical regulator. FEBS Journal. 2014b;281:3061-3078.

    Not in our library10.1111/febs.12843

  11. 11.

    de Bie P, Zaaroor-Regev D, Ciechanover A. Regulation of the polycomb protein RING1B ubiquitination by USP7. Biochemical and Biophysical Research Communications. 2010;400:389-395.

    Not in our library10.1016/j.bbrc.2010.08.082

  12. 12.

    Bold R. “Development of the proteasome inhibitor Velcade (Bortezomib)” by Julian Adams, Ph.D., and Michael Kauffman, M.D., Ph.D. Cancer Investigation. 2004;22:328-329.

    Not in our library10.1081/cnv-120030223

  13. 13.

    Bosanac I, Wertz IE, Pan B, Yu C, Kusam S, Lam C, Phu L, Phung Q, Maurer B, Arnott D, et al. Ubiquitin binding to A20 ZnF4 is required for modulation of NF-κB signaling. Molecular Cell. 2010;40:548-557.

    Not in our library10.1016/j.molcel.2010.10.009

  14. 14.

    Boudreaux DA, Maiti TK, Davies CW, Das C. Ubiquitin vinyl methyl ester binding orients the misaligned active site of the ubiquitin hydrolase UCHL1 into productive conformation. PNAS. 2010;107:9117-9122.

    Not in our library10.1073/pnas.0910870107

  15. 15.
    Association of promoter methylation of VGF and PGP9.5 with ovarian cancer progression. · 2013
    Not checked
  16. 16.

    Brummelkamp TR, Nijman SM, Dirac AM, Bernards R. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB. Nature. 2003;424:797-801.

    Not in our library10.1038/nature01811

  17. 17.

    Burnett B, Li F, Pittman RN. The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. Human Molecular Genetics. 2003;12:3195-3205.

    Not in our library10.1093/hmg/ddg344

  18. 18.

    Burska UL, Harle VJ, Coffey K, Darby S, Ramsey H, O'Neill D, Logan IR, Gaughan L, Robson CN. Deubiquitinating enzyme Usp12 is a novel co-activator of the androgen receptor. Journal of Biological Chemistry. 2013;288:32641-32650.

    Not in our library10.1074/jbc.m113.485912

  19. 19.

    Butler LR, Densham RM, Jia J, Garvin AJ, Stone HR, Shah V, Weekes D, Festy F, Beesley J, Morris JR. The proteasomal de-ubiquitinating enzyme POH1 promotes the double-strand DNA break response. EMBO Journal. 2012;31:3918-3934.

    Not in our library10.1038/emboj.2012.232

  20. 20.

    Carneiro AP, Reis CF, Morari EC, Maia YC, Nascimento R, Bonatto JM, de Souza MA, Goulart LR, Ward LS. A putative OTU domain-containing protein 1 deubiquitinating enzyme is differentially expressed in thyroid cancer and identifies less-aggressive tumours. British Journal of Cancer. 2014;111:551-558.

    Not in our library10.1038/bjc.2014.331

  21. 21.

    Chan JK, Greene WC. NF-κB/Rel: agonist and antagonist roles in HIV-1 latency. Current Opinion in HIV and AIDS. 2011;6:12-18.

    Not in our library10.1097/coh.0b013e32834124fd

  22. 22.

    Chanudet E, Ye H, Ferry J, Bacon CM, Adam P, Muller-Hermelink HK, Radford J, Pileri SA, Ichimura K, Collins VP, et al. A20 deletion is associated with copy number gain at the TNFA/B/C locus and occurs preferentially in translocation-negative MALT lymphoma of the ocular adnexa and salivary glands. Journal of Pathology. 2009;217:420-430.

    Not in our library10.1002/path.2466

  23. 23.

    Chauhan D, Tian Z, Nicholson B, Kumar KG, Zhou B, Carrasco R, McDermott JL, Leach CA, Fulcinniti M, Kodrasov MP, et al. A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell. 2012;22:345-358.

    Not in our library10.1016/j.ccr.2012.08.007

  24. 24.

    Chen ZJ. Ubiquitin signalling in the NF-κB pathway. Nature Cell Biology. 2005;7:758-765.

    Not in our library10.1038/ncb0805-758

  25. 25.

    Ching W, Koyuncu E, Singh S, Arbelo-Roman C, Hartl B, Kremmer E, Speiseder T, Meier C, Dobner T. A ubiquitin-specific protease possesses a decisive role for adenovirus replication and oncogene-mediated transformation. PLoS Pathogens. 2013;9:e1003273.

    Not in our library10.1371/journal.ppat.1003273

  26. 26.

    Chintharlapalli S, Papineni S, Ramaiah SK, Safe S. Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Research. 2007;67:2816-2823.

    Not in our library10.1158/0008-5472.can-06-3735

  27. 27.

    Chu IM, Hengst L, Slingerland JM. The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nature Reviews. Cancer. 2008;8:253-267.

    Not in our library10.1038/nrc2347

  28. 28.

    Ciechanover A. The ubiquitin proteolytic system and pathogenesis of human diseases: a novel platform for mechanism-based drug targeting. Biochemical Society Transactions. 2003;31:474-481.

    Not in our library10.1042/bst0310474

  29. 29.

    Ciechanover A. The ubiquitin proteolytic system: from an idea to the patient bed. Proceedings of the American Thoracic Society. 2006;3:21-31.

    Not in our library10.1513/pats.200510-106jh

  30. 30.

    Ciechanover A, Schwartz AL. The ubiquitin system: pathogenesis of human diseases and drug targeting. Biochimica et Biophysica Acta. 2004;1695:3-17.

    Not in our library10.1016/j.bbamcr.2004.09.018

  31. 31.

    Ciechanover A, Orian A, Schwartz AL. Ubiquitin-mediated proteolysis: biological regulation via destruction. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology. 2000;22:442-451.

    Not in our library10.1002/(sici)1521-1878(200005)22:5<442::aid-bies6>3.0.co;2-q

  32. 32.

    Clague MJ, Barsukov I, Coulson JM, Liu H, Rigden DJ, Urbe S. Deubiquitylases from genes to organism. Physiological Reviews. 2013;93:1289-1315.

    Not in our library10.1152/physrev.00002.2013

  33. 33.
    Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide · 2014
    No notice
  34. 34.

    Colland F, Formstecher E, Jacq X, Reverdy C, Planquette C, Conrath S, Trouplin V, Bianchi J, Aushev VN, Camonis J, et al. Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells. Molecular Cancer Therapeutics. 2009;8:2286-2295.

    Not in our library10.1158/1535-7163.mct-09-0097

  35. 35.

    Cooper EM, Cutcliffe C, Kristiansen TZ, Pandey A, Pickart CM, Cohen RE. K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1. EMBO Journal. 2009;28:621-631.

    Not in our library10.1038/emboj.2009.27

  36. 36.

    Curcio-Morelli C, Zavacki AM, Christofollete M, Gereben B, de Freitas BC, Harney JW, Li Z, Wu G, Bianco AC. Deubiquitination of type 2 iodothyronine deiodinase by von Hippel–Lindau protein-interacting deubiquitinating enzymes regulates thyroid hormone activation. Journal of Clinical Investigation. 2003;112:189-196.

    Not in our library10.1172/jci18348

  37. 37.
    Ubiquitin-specific peptidase 22, a histone deubiquitinating enzyme, is a novel poor prognostic factor for salivary adenoid cystic carcinoma. · 2014
    Not checked
  38. 38.

    D'Arcy P, Linder S. Proteasome deubiquitinases as novel targets for cancer therapy. International Journal of Biochemistry & Cell Biology. 2012;44:1729-1738.

    Not in our library10.1016/j.biocel.2012.07.011

  39. 39.

    Das C, Hoang QQ, Kreinbring CA, Luchansky SJ, Meray RK, Ray SS, Lansbury PT, Ringe D, Petsko GA. Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1. PNAS. 2006;103:4675-4680.

    Not in our library10.1073/pnas.0510403103

  40. 40.

    Davies CW, Chaney J, Korbel G, Ringe D, Petsko GA, Ploegh H, Das C. The co-crystal structure of ubiquitin carboxy-terminal hydrolase L1 (UCHL1) with a tripeptide fluoromethyl ketone (Z-VAE(OMe)-FMK). Bioorganic & Medicinal Chemistry Letters. 2012;22:3900-3904.

    Not in our library10.1016/j.bmcl.2012.04.124

  41. 41.

    Dean JL, Knudsen KE. The role of tumor suppressor dysregulation in prostate cancer progression. Current Drug Targets. 2013;14:460-471.

    Not in our library10.2174/1389450111314040007

  42. 42.

    Dentice M, Bandyopadhyay A, Gereben B, Callebaut I, Christoffolete MA, Kim BW, Nissim S, Mornon JP, Zavacki AM, Zeold A, et al. The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate. Nature Cell Biology. 2005;7:698-705.

    Not in our library10.1038/ncb1272

  43. 43.

    Dirac AM, Bernards R. The deubiquitinating enzyme USP26 is a regulator of androgen receptor signaling. Molecular Cancer Research. 2010;8:844-854.

    Not in our library10.1158/1541-7786.mcr-09-0424

  44. 44.

    Draker R, Sarcinella E, Cheung P. USP10 deubiquitylates the histone variant H2A.Z and both are required for androgen receptor-mediated gene activation. Nucleic Acids Research. 2011;39:3529-3542.

    Not in our library10.1093/nar/gkq1352

  45. 45.

    Du Z, Song J, Wang Y, Zhao Y, Guda K, Yang S, Kao HY, Xu Y, Willis J, Markowitz SD, et al. DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination. Science Signaling. 2010;3:ra80.

    Not in our library10.1126/scisignal.2001462

  46. 46.

    Du M, Yuan T, Schilter KF, Dittmar RL, Mackinnon A, Huang X, Tschannen M, Worthey E, Jacob H, Xia S, et al. Prostate cancer risk locus at 8q24 as a regulatory hub by physical interactions with multiple genomic loci across the genome. Human Molecular Genetics. 2015;24:154-166.

    Not in our library10.1093/hmg/ddu426

  47. 47.

    Eichhorn PJ, Rodon L, Gonzalez-Junca A, Dirac A, Gili M, Martinez-Saez E, Aura C, Barba I, Peg V, Prat A, et al. USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma. Nature Medicine. 2012;18:429-435.

    Not in our library10.1038/nm.2619

  48. 48.

    Espinosa-de-Los-Monteros-Franco VA, Martinez-Madrigal F, Ortiz-Hidalgo C. Granular cell tumor (Abrikossoff tumor) of the thyroid gland. Annals of Diagnostic Pathology. 2009;13:269-271.

    Not in our library10.1016/j.anndiagpath.2008.04.008

  49. 49.

    Evert BO, Araujo J, Vieira-Saecker AM, de Vos RA, Harendza S, Klockgether T, Wullner U. Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3, and histone deacetylation. Journal of Neuroscience. 2006;26:11474-11486.

    Not in our library10.1523/jneurosci.2053-06.2006

  50. 50.

    Faesen AC, Dirac AM, Shanmugham A, Ovaa H, Perrakis A, Sixma TK. Mechanism of USP7/HAUSP activation by its C-terminal ubiquitin-like domain and allosteric regulation by GMP-synthetase. Molecular Cell. 2011;44:147-159.

    Not in our library10.1016/j.molcel.2011.06.034

  51. 51.

    Fan YH, Cheng J, Vasudevan SA, Dou J, Zhang H, Patel RH, Ma IT, Rojas Y, Zhao Y, Yu Y, et al. USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis. Cell Death & Disease. 2013;4:e867.

    Not in our library10.1038/cddis.2013.400

  52. 52.

    Fang S, Weissman AM. A field guide to ubiquitylation. Cellular and Molecular Life Sciences. 2004;61:1546-1561.

    Not in our library10.1007/s00018-004-4129-5

  53. 53.

    Faustrup H, Bekker-Jensen S, Bartek J, Lukas J, Mailand N. USP7 counteracts SCFβTrCP – but not APCCdh1-mediated proteolysis of Claspin. Journal of Cell Biology. 2009;184:13-19.

    Not in our library10.1083/jcb.200807137

  54. 54.

    Fraile JM, Quesada V, Rodriguez D, Freije JM, Lopez-Otin C. Deubiquitinases in cancer: new functions and therapeutic options. Oncogene. 2012;31:2373-2388.

    Not in our library10.1038/onc.2011.443

  55. 55.

    Fu X, Creighton CJ, Biswal NC, Kumar V, Shea M, Herrera S, Contreras A, Gutierrez C, Wang T, Nanda S, et al. Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase. Breast Cancer Research. 2014;16:430.

    Not in our library10.1186/s13058-014-0430-x

  56. 56.

    Garolla A, Ferlin A, Vinanzi C, Roverato A, Sotti G, Artibani W, Foresta C. Molecular analysis of the androgen receptor gene in testicular cancer. Endocrine-Related Cancer. 2005;12:645-655.

    Not in our library10.1677/erc.1.00954

  57. 57.

    Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, Zeold A, Bianco AC. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocrine Reviews. 2008;29:898-938.

    Not in our library10.1210/er.2008-0019

  58. 58.

    Gheorgheosu D, Duicu O, Dehelean C, Soica C, Muntean D. Betulinic acid as a potent and complex antitumor phytochemical: a minireview. Anti-Cancer Agents in Medicinal Chemistry. 2014;14:936-945.

    Not in our library10.2174/1871520614666140223192148

  59. 59.

    Giovinazzi S, Sirleto P, Aksenova V, Morozov VM, Zori R, Reinhold WC, Ishov AM. Usp7 protects genomic stability by regulating Bub3. Oncotarget. 2014;5:3728-3742.

    Not in our library10.18632/oncotarget.1989

  60. 60.

    Glinsky GV. Death-from-cancer signatures and stem cell contribution to metastatic cancer. Cell Cycle. 2005;4:1171-1175.

    Not in our library10.4161/cc.4.9.2001

  61. 61.

    Glinsky GV. Genomic models of metastatic cancer: functional analysis of death-from-cancer signature genes reveals aneuploid, anoikis-resistant, metastasis-enabling phenotype with altered cell cycle control and activated polycomb group (PcG) protein chromatin silencing pathway. Cell Cycle. 2006;5:1208-1216.

    Not in our library10.4161/cc.5.11.2796

  62. 62.

    Glinsky GV, Berezovska O, Glinskii AB. Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. Journal of Clinical Investigation. 2005;115:1503-1521.

    Not in our library10.1172/jci23412

  63. 63.

    Graner E, Tang D, Rossi S, Baron A, Migita T, Weinstein LJ, Lechpammer M, Huesken D, Zimmermann J, Signoretti S, et al. The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer. Cancer Cell. 2004;5:253-261.

    Not in our library10.1016/s1535-6108(04)00055-8

  64. 64.

    Gusella JF, MacDonald ME. Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease. Nature Reviews. Neuroscience. 2000;1:109-115.

    Not in our library10.1038/35039051

  65. 65.

    Harhaj EW, Dixit VM. Regulation of NF-κB by deubiquitinases. Immunological Reviews. 2012;246:107-124.

    Not in our library10.1111/j.1600-065x.2012.01100.x

  66. 66.

    Hayashi M, Jono H, Shinriki S, Nakamura T, Guo J, Sueta A, Tomiguchi M, Fujiwara S, Yamamoto-Ibusuki M, Murakami K, et al. Clinical significance of CYLD downregulation in breast cancer. Breast Cancer Research and Treatment. 2014;143:447-457.

    Not in our library10.1007/s10549-013-2824-3

  67. 67.

    Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocrine Reviews. 2004;25:276-308.

    Not in our library10.1210/er.2002-0032

  68. 68.

    Hibi K, Liu Q, Beaudry GA, Madden SL, Westra WH, Wehage SL, Yang SC, Heitmiller RF, Bertelsen AH, Sidransky D, et al. Serial analysis of gene expression in non-small cell lung cancer. Cancer Research. 1998;58:5690-5694.

    Not in our library

  69. 69.

    Hibi K, Westra WH, Borges M, Goodman S, Sidransky D, Jen J. PGP9.5 as a candidate tumor marker for non-small-cell lung cancer. American Journal of Pathology. 1999;155:711-715.

    Not in our library10.1016/s0002-9440(10)65169-3

  70. 70.

    Hicke L. Protein regulation by monoubiquitin. Nature Reviews. Molecular Cell Biology. 2001;2:195-201.

    Not in our library10.1038/35056583

  71. 71.

    Hochstrasser M. Ubiquitin-dependent protein degradation. Annual Review of Genetics. 1996;30:405-439.

    Not in our library10.1146/annurev.genet.30.1.405

  72. 72.

    Hofmann K, Falquet L. A ubiquitin-interacting motif conserved in components of the proteasomal and lysosomal protein degradation systems. Trends in Biochemical Sciences. 2001;26:347-350.

    Not in our library10.1016/s0968-0004(01)01835-7

  73. 73.

    Holland AJ, Cleveland DW. The deubiquitinase USP44 is a tumor suppressor that protects against chromosome missegregation. Journal of Clinical Investigation. 2012;122:4325-4328.

    Not in our library10.1172/jci66420

  74. 74.

    Holowaty MN, Zeghouf M, Wu H, Tellam J, Athanasopoulos V, Greenblatt J, Frappier L. Protein profiling with Epstein–Barr nuclear antigen-1 reveals an interaction with the herpesvirus-associated ubiquitin-specific protease HAUSP/USP7. Journal of Biological Chemistry. 2003;278:29987-29994.

    Not in our library10.1074/jbc.m303977200

  75. 75.

    van der Horst A, de Vries-Smits AM, Brenkman AB, van Triest MH, van den Broek N, Colland F, Maurice MM, Burgering BM. FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nature Cell Biology. 2006;8:1064-1073.

    Not in our library10.1038/ncb1469

  76. 76.

    Howell VM, Gill A, Clarkson A, Nelson AE, Dunne R, Delbridge LW, Robinson BG, Teh BT, Gimm O, Marsh DJ. Accuracy of combined protein gene product 9.5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma. Journal of Clinical Endocrinology and Metabolism. 2009;94:434-441.

    Not in our library10.1210/jc.2008-1740

  77. 77.

    Hu M, Li P, Li M, Li W, Yao T, Wu JW, Gu W, Cohen RE, Shi Y. Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell. 2002;111:1041-1054.

    Not in our library10.1016/s0092-8674(02)01199-6

  78. 78.

    Hu M, Li P, Song L, Jeffrey PD, Chenova TA, Wilkinson KD, Cohen RE, Shi Y. Structure and mechanisms of the proteasome-associated deubiquitinating enzyme USP14. EMBO Journal. 2005;24:3747-3756.

    Not in our library10.1038/sj.emboj.7600832

  79. 79.

    Hymowitz SG, Wertz IE. A20: from ubiquitin editing to tumour suppression. Nature Reviews. Cancer. 2010;10:332-341.

    Not in our library10.1038/nrc2775

  80. 80.

    Iwai K, Tokunaga F. Linear polyubiquitination: a new regulator of NF-κB activation. EMBO Reports. 2009;10:706-713.

    Not in our library10.1038/embor.2009.144

  81. 81.

    Jager W, Santag S, Weidner-Glunde M, Gellermann E, Kati S, Pietrek M, Viejo-Borbolla A, Schulz TF. The ubiquitin-specific protease USP7 modulates the replication of Kaposi's sarcoma-associated herpesvirus latent episomal DNA. Journal of Virology. 2012;86:6745-6757.

    Not in our library10.1128/jvi.06840-11

  82. 82.

    Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA, Ishov AM, Tommerup N, Vissing H, Sekido Y, et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene. 1998;16:1097-1112.

    Not in our library10.1038/sj.onc.1201861

  83. 83.

    Ji Z, Mohammed H, Webber A, Ridsdale J, Han N, Carroll JS, Sharrocks AD. The forkhead transcription factor FOXK2 acts as a chromatin targeting factor for the BAP1-containing histone deubiquitinase complex. Nucleic Acids Research. 2014;42:6232-6242.

    Not in our library10.1093/nar/gku274

  84. 84.

    Jin C, Yu W, Lou X, Zhou F, Han X, Zhao N, Lin B. UCHL1 is a putative tumor suppressor in ovarian cancer cells and contributes to cisplatin resistance. Journal of Cancer. 2013;4:662-670.

    Not in our library10.7150/jca.6641

  85. 85.

    Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333-339.

    Not in our library10.1038/nature12634

  86. 86.

    Kato N, Yamamoto H, Adachi Y, Ohashi H, Taniguchi H, Suzuki H, Nakazawa M, Kaneto H, Sasaki S, Imai K, et al. Cancer detection by ubiquitin carboxyl-terminal esterase L1 methylation in pancreatobiliary fluids. World Journal of Gastroenterology. 2013;19:1718-1727.

    Not in our library10.3748/wjg.v19.i11.1718

  87. 87.

    Khoronenkova SV, Dianov GL. USP7S-dependent inactivation of Mule regulates DNA damage signalling and repair. Nucleic Acids Research. 2013;41:1750-1756.

    Not in our library10.1093/nar/gks1359

  88. 88.

    Kim JH, Park KC, Chung SS, Bang O, Chung CH. Deubiquitinating enzymes as cellular regulators. Journal of Biochemistry. 2003;134:9-18.

    Not in our library10.1093/jb/mvg107

  89. 89.

    van der Knaap JA, Kumar BR, Moshkin YM, Langenberg K, Krijgsveld J, Heck AJ, Karch F, Verrijzer CP. GMP synthetase stimulates histone H2B deubiquitylation by the epigenetic silencer USP7. Molecular Cell. 2005;17:695-707.

    Not in our library10.1016/j.molcel.2005.02.013

  90. 90.

    van der Knaap JA, Kozhevnikova E, Langenberg K, Moshkin YM, Verrijzer CP. Biosynthetic enzyme GMP synthetase cooperates with ubiquitin-specific protease 7 in transcriptional regulation of ecdysteroid target genes. Molecular and Cellular Biology. 2009;30:736-744.

    Not in our library10.1128/mcb.01121-09

  91. 91.

    Köhler A, Zimmerman E, Schneider M, Hurt E, Zheng N. Structural basis for assembly and activation of the heterotetrameric SAGA histone H2B deubiquitinase module. Cell. 2010;141:606-617.

    Not in our library10.1016/j.cell.2010.04.026

  92. 92.

    Komander D. The emerging complexity of protein ubiquitination. Biochemical Society Transactions. 2009;37:937-953.

    Not in our library10.1042/bst0370937

  93. 93.

    Komander D, Barford D. Structure of the A20 OTU domain and mechanistic insights into deubiquitination. Biochemical Journal. 2008;409:77-85.

    Not in our library10.1042/bj20071399

  94. 94.

    Komander D, Lord CJ, Scheel H, Swift S, Hofmann K, Ashworth A, Barford D. The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module. Molecular Cell. 2008;29:451-464.

    Not in our library10.1016/j.molcel.2007.12.018

  95. 95.

    Kon N, Kobayashi Y, Li M, Brooks CL, Ludwig T, Gu W. Inactivation of HAUSP in vivo modulates p53 function. Oncogene. 2010;29:1270-1279.

    Not in our library10.1038/onc.2009.427

  96. 96.

    Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, Wallach D, Courtois G. The tumour suppressor CYLD negatively regulates NF-κB signalling by deubiquitination. Nature. 2003;424:801-805.

    Not in our library10.1038/nature01802

  97. 97.

    Krikos A, Laherty CD, Dixit VM. Transcriptional activation of the tumor necrosis factor alpha-inducible zinc finger protein, A20, is mediated by κB elements. Journal of Biological Chemistry. 1992;267:17971-17976.

    Not in our library

  98. 98.

    Kulathu Y, Garcia FJ, Mevissen TE, Busch M, Arnaudo N, Carroll KS, Barford D, Komander D. Regulation of A20 and other OTU deubiquitinases by reversible oxidation. Nature Communications. 2013;4:1569.

    Not in our library10.1038/ncomms2567

  99. 99.

    Lander GC, Estrin E, Matyskiela ME, Bashore C, Nogales E, Martin A. Complete subunit architecture of the proteasome regulatory particle. Nature. 2012;482:186-191.

    Not in our library10.1038/nature10774

  100. 100.

    Larsen CN, Krantz BA, Wilkinson KD. Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal hydrolases. Biochemistry. 1998;37:3358-3368.

    Not in our library10.1021/bi972274d

  101. 101.

    Laurell C, Velazquez-Fernandez D, Lindsten K, Juhlin C, Enberg U, Geli J, Hoog A, Kjellman M, Lundeberg J, Hamberger B, et al. Transcriptional profiling enables molecular classification of adrenocortical tumours. European Journal of Endocrinology. 2009;161:141-152.

    Not in our library10.1530/eje-09-0068

  102. 102.

    Lee HR, Choi WC, Lee S, Hwang J, Hwang E, Guchhait K, Haas J, Toth Z, Jeon YH, Oh TK, et al. Bilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein. Nature Structural & Molecular Biology. 2011;18:1336-1344.

    Not in our library10.1038/nsmb.2142

  103. 103.

    Leiblich A, Cross SS, Catto JW, Pesce G, Hamdy FC, Rehman I. Human prostate cancer cells express neuroendocrine cell markers PGP 9.5 and chromogranin A. Prostate. 2007;67:1761-1769.

    Not in our library10.1002/pros.20654

  104. 104.

    Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T, et al. The ubiquitin pathway in Parkinson's disease. Nature. 1998;395:451-452.

    Not in our library10.1038/26652

  105. 105.

    Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature. 2002a;416:648-653.

    Not in our library10.1038/nature737

  106. 106.

    Li Z, Wang D, Na X, Schoen SR, Messing EM, Wu G. Identification of a deubiquitinating enzyme subfamily as substrates of the von Hippel–Lindau tumor suppressor. Biochemical and Biophysical Research Communications. 2002b;294:700-709.

    Not in our library10.1016/s0006-291x(02)00534-x

  107. 107.

    Li Z, Na X, Wang D, Schoen SR, Messing EM, Wu G. Ubiquitination of a novel deubiquitinating enzyme requires direct binding to von Hippel–Lindau tumor suppressor protein. Journal of Biological Chemistry. 2002c;277:4656-4662.

    Not in our library10.1074/jbc.m108269200

  108. 108.

    Li Z, Wang D, Messing EM, Wu G. VHL protein-interacting deubiquitinating enzyme 2 deubiquitinates and stabilizes HIF-1α. EMBO Reports. 2005;6:373-378.

    Not in our library10.1038/sj.embor.7400377

  109. 109.

    Li J, Olson LM, Zhang Z, Li L, Bidder M, Nguyen L, Pfeifer J, Rader JS. Differential display identifies overexpression of the USP36 gene, encoding a deubiquitinating enzyme, in ovarian cancer. International Journal of Medical Sciences. 2008;5:133-142.

    Not in our library10.7150/ijms.5.133

  110. 110.

    Li L, Wen S, Wang B, Gao W, Zhang W, Meng X, Yang L, Kong L. [Expression of cancer stem cell marker USP22 in laryngeal squamous cell carcinoma]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2014;49:479-482.

    Not in our library

  111. 111.

    Lin SC, Chung JY, Lamothe B, Rajashankar K, Lu M, Lo YC, Lam AY, Darnay BG, Wu H. Molecular basis for the unique deubiquitinating activity of the NF-κB inhibitor A20. Journal of Molecular Biology. 2008;376:526-540.

    Not in our library10.1016/j.jmb.2007.11.092

  112. 112.

    Lin Z, Yang H, Kong Q, Li J, Lee SM, Gao B, Dong H, Wei J, Song J, Zhang DD, et al. USP22 antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required for mouse embryonic development. Molecular Cell. 2012;46:484-494.

    Not in our library10.1016/j.molcel.2012.03.024

  113. 113.

    Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT. The UCH-L1 gene encodes two opposing enzymatic activities that affect α-synuclein degradation and Parkinson's disease susceptibility. Cell. 2002;111:209-218.

    Not in our library10.1016/s0092-8674(02)01012-7

  114. 114.

    Liu Y, Yang Y, Xu H, Dong X. Implication of USP22 in the regulation of BMI-1, c-Myc, p16INK4a, p14ARF, and cyclin D2 expression in primary colorectal carcinomas. Diagnostic Molecular Pathology. 2010;19:194-200.

    Not in our library10.1097/pdm.0b013e3181e202f2

  115. 115.

    Liu L, Zhao Q, Liang X, Du G, Lu L, Dong J, Han H. [Expression of neuronal marker protein gene product 9.5 and its clinicopathologic significance in breast cancer]. Zhonghua Bing Li Xue Za Zhi. 2014;43:318-320.

    Not in our library

  116. 116.

    Lu Y, Bedard N, Chevalier S, Wing SS. Identification of distinctive patterns of USP19-mediated growth regulation in normal and malignant cells. PLoS ONE. 2011;6:e15936.

    Not in our library10.1371/journal.pone.0015936

  117. 117.

    Lu H, Wang X, Urvalek AM, Li T, Xie H, Yu L, Zhao J. Transformation of human ovarian surface epithelial cells by Kruppel-like factor 8. Oncogene. 2014;33:10-18.

    Not in our library10.1038/onc.2012.545

  118. 118.

    Luise C, Capra M, Donzelli M, Mazzarol G, Jodice MG, Nuciforo P, Viale G, Di Fiore PP, Confalonieri S. An atlas of altered expression of deubiquitinating enzymes in human cancer. PLoS ONE. 2011;6:e15891.

    Not in our library10.1371/journal.pone.0015891

  119. 119.

    Ma Z, Gao X, Zhao W, Li Y, Li C. Relationship between expression of Pad1 homologue and multidrug resistance of idiopathic nephrotic syndrome. Pediatrics International. 2009;51:732-735.

    Not in our library10.1111/j.1442-200x.2009.02845.x

  120. 120.

    Machida YJ, Machida Y, Vashisht AA, Wohlschlegel JA, Dutta A. The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1. Journal of Biological Chemistry. 2009;284:34179-34188.

    Not in our library10.1074/jbc.m109.046755

  121. 121.

    Maertens GN, El Messaoudi-Aubert S, Elderkin S, Hiom K, Peters G. Ubiquitin-specific proteases 7 and 11 modulate polycomb regulation of the INK4a tumour suppressor. EMBO Journal. 2010;29:2553-2565.

    Not in our library10.1038/emboj.2010.129

  122. 122.

    Mao Y, Senic-Matuglia F, Di Fiore PP, Polo S, Hodsdon ME, De Camilli P. Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain. PNAS. 2005;102:12700-12705.

    Not in our library10.1073/pnas.0506344102

  123. 123.

    Massoumi R. CYLD: a deubiquitination enzyme with multiple roles in cancer. Future Oncology. 2011;7:285-297.

    Not in our library10.2217/fon.10.187

  124. 124.

    Masuya D, Huang C, Liu D, Nakashima T, Yokomise H, Ueno M, Nakashima N, Sumitomo S. The HAUSP gene plays an important role in non-small cell lung carcinogenesis through p53-dependent pathways. Journal of Pathology. 2006;208:724-732.

    Not in our library10.1002/path.1931

  125. 125.

    Meredith M, Orr A, Everett R. Herpes simplex virus type 1 immediate-early protein Vmw110 binds strongly and specifically to a 135-kDa cellular protein. Virology. 1994;200:457-469.

    Not in our library10.1006/viro.1994.1209

  126. 126.

    Meulmeester E, Maurice MM, Boutell C, Teunisse AF, Ovaa H, Abraham TE, Dirks RW, Jochemsen AG. Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2. Molecular Cell. 2005;18:565-576.

    Not in our library10.1016/j.molcel.2005.04.024

  127. 127.

    Miranda M, Sorkin A. Regulation of receptors and transporters by ubiquitination: new insights into surprisingly similar mechanisms. Molecular Interventions. 2007;7:157-167.

    Not in our library10.1124/mi.7.3.7

  128. 128.

    Misaghi S, Ottosen S, Izrael-Tomasevic A, Arnott D, Lamkanfi M, Lee J, Liu J, O'Rourke K, Dixit VM, Wilson AC. Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1. Molecular and Cellular Biology. 2009;29:2181-2192.

    Not in our library10.1128/mcb.01517-08

  129. 129.

    Morotti A, Panuzzo C, Crivellaro S, Pergolizzi B, Familiari U, Berger AH, Saglio G, Pandolfi PP. BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP. Leukemia. 2014;28:1326-1333.

    Not in our library10.1038/leu.2013.370

  130. 130.

    Mosbech A, Lukas C, Bekker-Jensen S, Mailand N. The deubiquitylating enzyme USP44 counteracts the DNA double-strand break response mediated by the RNF8 and RNF168 ubiquitin ligases. Journal of Biological Chemistry. 2013;288:16579-16587.

    Not in our library10.1074/jbc.m113.459917

  131. 131.

    Nanao MH, Tcherniuk SO, Chroboczek J, Dideberg O, Dessen A, Balakirev MY. Crystal structure of human otubain 2. EMBO Reports. 2004;5:783-788.

    Not in our library10.1038/sj.embor.7400201

  132. 132.

    Nicastro G, Menon RP, Masino L, Knowles PP, McDonald NQ, Pastore A. The solution structure of the Josephin domain of ataxin-3: structural determinants for molecular recognition. PNAS. 2005;102:10493-10498.

    Not in our library10.1073/pnas.0501732102

  133. 133.

    Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R. A genomic and functional inventory of deubiquitinating enzymes. Cell. 2005;123:773-786.

    Not in our library10.1016/j.cell.2005.11.007

  134. 134.

    Okochi-Takada E, Nakazawa K, Wakabayashi M, Mori A, Ichimura S, Yasugi T, Ushijima T. Silencing of the UCHL1 gene in human colorectal and ovarian cancers. International Journal of Cancer. Journal International du Cancer. 2006;119:1338-1344.

    Not in our library10.1002/ijc.22025

  135. 135.

    Pal A, Young MA, Donato NJ. Emerging potential of therapeutic targeting of ubiquitin-specific proteases in the treatment of cancer. Cancer Research. 2014;74:4955-4966.

    Not in our library10.1158/0008-5472.can-14-1211

  136. 136.

    Panier S, Durocher D. Regulatory ubiquitylation in response to DNA double-strand breaks. DNA Repair. 2009;8:436-443.

    Not in our library10.1016/j.dnarep.2009.01.013

  137. 137.

    Parviainen H, Schrade A, Kiiveri S, Prunskaite-Hyyrylainen R, Haglund C, Vainio S, Wilson DB, Arola J, Heikinheimo M. Expression of Wnt and TGF-β pathway components and key adrenal transcription factors in adrenocortical tumors: association to carcinoma aggressiveness. Pathology, Research and Practice. 2013;209:503-509.

    Not in our library10.1016/j.prp.2013.06.002

  138. 138.

    Pathare GR, Nagy I, Sledz P, Anderson DJ, Zhou HJ, Pardon E, Steyaert J, Forster F, Bracher A, Baumeister W. Crystal structure of the proteasomal deubiquitylation module Rpn8–Rpn11. PNAS. 2014;111:2984-2989.

    Not in our library10.1073/pnas.1400546111

  139. 139.

    Piao S, Liu Y, Hu J, Guo F, Ma J, Sun Y, Zhang B. USP22 is useful as a novel molecular marker for predicting disease progression and patient prognosis of oral squamous cell carcinoma. PLoS ONE. 2012;7:e42540.

    Not in our library10.1371/journal.pone.0042540

  140. 140.

    Piao S, Ma J, Wang W, Liu Y, Zhang M, Chen H, Guo F, Zhang B. Increased expression of USP22 is associated with disease progression and patient prognosis of salivary duct carcinoma. Oral Oncology. 2013;49:796-801.

    Not in our library10.1016/j.oraloncology.2013.03.454

  141. 141.

    Pickart CM. Mechanisms underlying ubiquitination. Annual Review of Biochemistry. 2001;70:503-533.

    Not in our library10.1146/annurev.biochem.70.1.503

  142. 142.

    Planchon SM, Waite KA, Eng C. The nuclear affairs of PTEN. Journal of Cell Science. 2008;121:249-253.

    Not in our library10.1242/jcs.022459

  143. 143.

    Priolo C, Tang D, Brahamandan M, Benassi B, Sicinska E, Ogino S, Farsetti A, Porrello A, Finn S, Zimmermann J, et al. The isopeptidase USP2a protects human prostate cancer from apoptosis. Cancer Research. 2006;66:8625-8632.

    Not in our library10.1158/0008-5472.can-06-1374

  144. 144.

    Reddy BA, van der Knaap JA, Bot AG, Mohd-Sarip A, Dekkers DH, Timmermans MA, Martens JW, Demmers JA, Verrijzer CP. Nucleotide biosynthetic enzyme GMP synthase is a TRIM21-controlled relay of p53 stabilization. Molecular Cell. 2014;53:458-470.

    Not in our library10.1016/j.molcel.2013.12.017

  145. 145.

    Reiner T, Parrondo R, de Las Pozas A, Palenzuela D, Perez-Stable C. Betulinic acid selectively increases protein degradation and enhances prostate cancer-specific apoptosis: possible role for inhibition of deubiquitinase activity. PLoS ONE. 2013;8:e56234.

    Not in our library10.1371/journal.pone.0056234

  146. 146.

    Renatus M, Parrado SG, D'Arcy A, Eidhoff U, Gerhartz B, Hassiepen U, Pierrat B, Riedl R, Vinzenz D, Worpenberg S, et al. Structural basis of ubiquitin recognition by the deubiquitinating protease USP2. Structure. 2006;14:1293-1302.

    Not in our library10.1016/j.str.2006.06.012

  147. 147.

    Reverdy C, Conrath S, Lopez R, Planquette C, Atmanene C, Collura V, Harpon J, Battaglia V, Vivat V, Sippl W, et al. Discovery of specific inhibitors of human USP7/HAUSP deubiquitinating enzyme. Chemistry & Biology. 2012;19:467-477.

    Not in our library10.1016/j.chembiol.2012.02.007

  148. 148.

    Reyes-Turcu FE, Wilkinson KD. Polyubiquitin binding and disassembly by deubiquitinating enzymes. Chemical Reviews. 2009;109:1495-1508.

    Not in our library10.1021/cr800470j

  149. 149.

    Rode J, Dhillon AP, Doran JF, Jackson P, Thompson RJ. PGP 9.5, a new marker for human neuroendocrine tumours. Histopathology. 1985;9:147-158.

    Not in our library10.1111/j.1365-2559.1985.tb02431.x

  150. 150.

    Sacco JJ, Yau TY, Darling S, Patel V, Liu H, Urbe S, Clague MJ, Coulson JM. The deubiquitylase ataxin-3 restricts PTEN transcription in lung cancer cells. Oncogene. 2014;33:4265-4272.

    Not in our library10.1038/onc.2013.512

  151. 151.

    Saito K, Kigawa T, Koshiba S, Sato K, Matsuo Y, Sakamoto A, Takagi T, Shirouzu M, Yabuki T, Nunokawa E, et al. The CAP-Gly domain of CYLD associates with the proline-rich sequence in NEMO/IKKγ. Structure. 2004;12:1719-1728.

    Not in our library10.1016/j.str.2004.07.012

  152. 152.

    Salsman J, Jagannathan M, Paladino P, Chan PK, Dellaire G, Raught B, Frappier L. Proteomic profiling of the human cytomegalovirus UL35 gene products reveals a role for UL35 in the DNA repair response. Journal of Virology. 2012;86:806-820.

    Not in our library10.1128/jvi.05442-11

  153. 153.

    Samara NL, Datta AB, Berndsen CE, Zhang X, Yao T, Cohen RE, Wolberger C. Structural insights into the assembly and function of the SAGA deubiquitinating module. Science. 2010;328:1025-1029.

    Not in our library10.1126/science.1190049

  154. 154.

    Samara NL, Ringel AE, Wolberger C. A role for intersubunit interactions in maintaining SAGA deubiquitinating module structure and activity. Structure. 2012;20:1414-1424.

    Not in our library10.1016/j.str.2012.05.015

  155. 155.

    Saridakis V, Sheng Y, Sarkari F, Holowaty MN, Shire K, Nguyen T, Zhang RG, Liao J, Lee W, Edwards AM, et al. Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein–Barr nuclear antigen 1 implications for EBV-mediated immortalization. Molecular Cell. 2005;18:25-36.

    Not in our library10.1016/j.molcel.2005.02.029

  156. 156.

    Sarkari F, Sanchez-Alcaraz T, Wang S, Holowaty MN, Sheng Y, Frappier L. EBNA1-mediated recruitment of a histone H2B deubiquitylating complex to the Epstein–Barr virus latent origin of DNA replication. PLoS Pathogens. 2009;5:e1000624.

    Not in our library10.1371/journal.ppat.1000624

  157. 157.

    Sarkari F, La Delfa A, Arrowsmith CH, Frappier L, Sheng Y, Saridakis V. Further insight into substrate recognition by USP7: structural and biochemical analysis of the HdmX and Hdm2 interactions with USP7. Journal of Molecular Biology. 2010;402:825-837.

    Not in our library10.1016/j.jmb.2010.08.017

  158. 158.

    Sarkari F, Wheaton K, La Delfa A, Mohamed M, Shaikh F, Khatun R, Arrowsmith CH, Frappier L, Saridakis V, Sheng Y. Ubiquitin-specific protease 7 is a regulator of ubiquitin-conjugating enzyme UbE2E1. Journal of Biological Chemistry. 2013;288:16975-16985.

    Not in our library10.1074/jbc.m113.469262

  159. 159.

    Sato Y, Yoshikawa A, Yamagata A, Mimura H, Yamashita M, Ookata K, Nureki O, Iwai K, Komada M, Fukai S. Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains. Nature. 2008;455:358-362.

    Not in our library10.1038/nature07254

  160. 160.

    Scaglione KM, Zavodszky E, Todi SV, Patury S, Xu P, Rodriguez-Lebron E, Fischer S, Konen J, Djarmati A, Peng J, et al. Ube2w and ataxin-3 coordinately regulate the ubiquitin ligase CHIP. Molecular Cell. 2011;43:599-612.

    Not in our library10.1016/j.molcel.2011.05.036

  161. 161.

    Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S, Wilm M, Muir TW, Muller J. Histone H2A deubiquitinase activity of the polycomb repressive complex PR-DUB. Nature. 2010;465:243-247.

    Not in our library10.1038/nature08966

  162. 162.

    Schrecengost RS, Dean JL, Goodwin JF, Schiewer MJ, Urban MW, Stanek TJ, Sussman RT, Hicks JL, Birbe RC, Draganova-Tacheva RA, et al. USP22 regulates oncogenic signaling pathways to drive lethal cancer progression. Cancer Research. 2014;74:272-286.

    Not in our library10.1158/0008-5472.can-13-1954

  163. 163.

    Schweitzer K, Bozko PM, Dubiel W, Naumann M. CSN controls NF-κB by deubiquitinylation of IκBα. EMBO Journal. 2007;26:1532-1541.

    Not in our library10.1038/sj.emboj.7601600

  164. 164.

    Shanmugam I, Abbas M, Ayoub F, Mirabal S, Bsaili M, Caulder EK, Weinstock DM, Tomkinson AE, Hromas R, Shaheen M. Ubiquitin-specific peptidase 20 regulates Rad17 stability, checkpoint kinase 1 phosphorylation and DNA repair by homologous recombination. Journal of Biological Chemistry. 2014;289:22739-22748.

    Not in our library10.1074/jbc.m114.550459

  165. 165.

    Shembade N, Pujari R, Harhaj NS, Abbott DW, Harhaj EW. The kinase IKKα inhibits activation of the transcription factor NF-κB by phosphorylating the regulatory molecule TAX1BP1. Nature Immunology. 2011;12:834-843.

    Not in our library10.1038/ni.2066

  166. 166.

    Sheng Y, Saridakis V, Sarkari F, Duan S, Wu T, Arrowsmith CH, Frappier L. Molecular recognition of p53 and MDM2 by USP7/HAUSP. Nature Structural & Molecular Biology. 2006;13:285-291.

    Not in our library10.1038/nsmb1067

  167. 167.

    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: A Cancer Journal for Clinicians. 2014;64:9-29.

    Not in our library10.3322/caac.21208

  168. 168.

    Sloane MA, Wong JW, Perera D, Nunez AC, Pimanda JE, Hawkins NJ, Sieber OM, Bourke MJ, Hesson LB, Ward RL. Epigenetic inactivation of the candidate tumor suppressor USP44 is a frequent and early event in colorectal neoplasia. Epigenetics. 2014;9:1092-1100.

    Not in our library10.4161/epi.29222

  169. 169.

    Smit JJ, Sixma TK. RBR E3-ligases at work. EMBO Reports. 2014;15:142-154.

    Not in our library10.1002/embr.201338166

  170. 170.

    Song MS, Salmena L, Carracedo A, Egia A, Lo-Coco F, Teruya-Feldstein J, Pandolfi PP. The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network. Nature. 2008;455:813-817.

    Not in our library10.1038/nature07290

  171. 171.

    Spataro V, Simmen K, Realini CA. The essential 26S proteasome subunit Rpn11 confers multidrug resistance to mammalian cells. Anticancer Research. 2002;22:3905-3909.

    Not in our library

  172. 172.
    RBR E3 ubiquitin ligases: new structures, new insights, new questions · 2014
    No notice
  173. 173.

    Stanley JA, Aruldhas MM, Chandrasekaran M, Neelamohan R, Suthagar E, Annapoorna K, Sharmila S, Jayakumar J, Jayaraman G, Srinivasan N, et al. Androgen receptor expression in human thyroid cancer tissues: a potential mechanism underlying the gender bias in the incidence of thyroid cancers. Journal of Steroid Biochemistry and Molecular Biology. 2012;130:105-124.

    Not in our library10.1016/j.jsbmb.2012.02.004

  174. 174.

    Steele JM. Carfilzomib: a new proteasome inhibitor for relapsed or refractory multiple myeloma. Journal of Oncology Pharmacy Practice. 2013;19:348-354.

    Not in our library10.1177/1078155212470388

  175. 175.

    Stevenson LF, Sparks A, Allende-Vega N, Xirodimas DP, Lane DP, Saville MK. The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO Journal. 2007;26:976-986.

    Not in our library10.1038/sj.emboj.7601567

  176. 176.

    Sun T, Lee GS, Oh WK, Pomerantz M, Yang M, Xie W, Freedman ML, Kantoff PW. Single-nucleotide polymorphisms in p53 pathway and aggressiveness of prostate cancer in a Caucasian population. Clinical Cancer Research. 2010;16:5244-5251.

    Not in our library10.1158/1078-0432.ccr-10-1261

  177. 177.

    Takano T, Miyauchi A, Matsuzuka F, Yoshida H, Nakata Y, Kuma K, Amino N. PGP9.5 mRNA could contribute to the molecular-based diagnosis of medullary thyroid carcinoma. European Journal of Cancer. 2004;40:614-618.

    Not in our library10.1016/j.ejca.2003.11.016

  178. 178.

    Terzic J, Marinovic-Terzic I, Ikeda F, Dikic I. Ubiquitin signals in the NF-κB pathway. Biochemical Society Transactions. 2007;35:942-945.

    Not in our library10.1042/bst0350942

  179. 179.

    Tezel E, Hibi K, Nagasaka T, Nakao A. PGP9.5 as a prognostic factor in pancreatic cancer. Clinical Cancer Research. 2000;6:4764-4767.

    Not in our library

  180. 180.

    Thompson RJ, Doran JF, Jackson P, Dhillon AP, Rode J. PGP9.5 – a new marker for vertebrate neurons and neuroendocrine cells. Brain Research. 1983;278:224-228.

    Not in our library10.1016/0006-8993(83)90241-x

  181. 181.

    Tokunaga F, Nishimasu H, Ishitani R, Goto E, Noguchi T, Mio K, Kamei K, Ma A, Iwai K, Nureki O. Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-κB regulation. EMBO Journal. 2012;31:3856-3870.

    Not in our library10.1038/emboj.2012.241

  182. 182.

    Tomita T. PGP 9.5 immunocytochemical staining for pancreatic endocrine tumors. Islets. 2013;5:122-128.

    Not in our library10.4161/isl.25351

  183. 183.

    Tootee A, Hasani-Ranjbar S. Von Hippel–Lindau disease: a new approach to an old problem. International Journal of Endocrinology and Metabolism. 2012;10:619-624.

    Not in our library10.5812/ijem.4510

  184. 184.

    Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G. CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by TNFR family members. Nature. 2003;424:793-796.

    Not in our library10.1038/nature01803

  185. 185.

    Tsirlin A, Oo Y, Sharma R, Kansara A, Gliwa A, Banerji MA. Pheochromocytoma: a review. Maturitas. 2014;77:229-238.

    Not in our library10.1016/j.maturitas.2013.12.009

  186. 186.

    Ummanni R, Jost E, Braig M, Lohmann F, Mundt F, Barett C, Schlomm T, Sauter G, Senff T, Bokemeyer C, et al. Ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) is a potential tumour suppressor in prostate cancer and is frequently silenced by promoter methylation. Molecular Cancer. 2011;10:129.

    Not in our library10.1186/1476-4598-10-129

  187. 187.

    Uras IZ, List T, Nijman SM. Ubiquitin-specific protease 4 inhibits mono-ubiquitination of the master growth factor signaling kinase PDK1. PLoS ONE. 2012;7:e31003.

    Not in our library10.1371/journal.pone.0031003

  188. 188.

    Velazquez-Fernandez D, Laurell C, Geli J, Hoog A, Odeberg J, Kjellman M, Lundeberg J, Hamberger B, Nilsson P, Backdahl M. Expression profiling of adrenocortical neoplasms suggests a molecular signature of malignancy. Surgery. 2005;138:1087-1094.

    Not in our library10.1016/j.surg.2005.09.031

  189. 189.

    Vendrell JA, Ghayad S, Ben-Larbi S, Dumontet C, Mechti N, Cohen PA. A20/TNFAIP3, a new estrogen-regulated gene that confers tamoxifen resistance in breast cancer cells. Oncogene. 2007;26:4656-4667.

    Not in our library10.1038/sj.onc.1210269

  190. 190.

    Ventii KH, Devi NS, Friedrich KL, Chernova TA, Tighiouart M, Van Meir EG, Wilkinson KD. BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization. Cancer Research. 2008;68:6953-6962.

    Not in our library10.1158/0008-5472.can-08-0365

  191. 191.

    Verstrepen L, Verhelst K, Carpentier I, Beyaert R. TAX1BP1, a ubiquitin-binding adaptor protein in innate immunity and beyond. Trends in Biochemical Sciences. 2011;36:347-354.

    Not in our library10.1016/j.tibs.2011.03.004

  192. 192.

    Wang YZ, Wong YC. Oncogenes and tumor suppressor genes in prostate cancer: a review. Urologic Oncology. 1997;3:41-46.

    Not in our library10.1016/s1078-1439(97)00021-5

  193. 193.

    Wang G, Gao Y, Li L, Jin G, Cai Z, Chao JI, Lin HK. K63-linked ubiquitination in kinase activation and cancer. Frontiers in Oncology. 2012;2:5.

    Not in our library10.3389/fonc.2012.00005

  194. 194.

    Wang H, Li YP, Chen JH, Yuan SF, Wang L, Zhang JL, Yao Q, Li NL, Bian JF, Fan J, et al. Prognostic significance of USP22 as an oncogene in papillary thyroid carcinoma. Tumour Biology. 2013;34:1635-1639.

    Not in our library10.1007/s13277-013-0696-0

  195. 195.

    Wang L, Chen YJ, Xu K, Wang YY, Shen XZ, Tu RQ. High expression of UCH37 is significantly associated with poor prognosis in human epithelial ovarian cancer. Tumour Biology. 2014;35:11427-11433.

    Not in our library10.1007/s13277-014-2446-3

  196. 196.

    Warrick JM, Morabito LM, Bilen J, Gordesky-Gold B, Faust LZ, Paulson HL, Bonini NM. Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism. Molecular Cell. 2005;18:37-48.

    Not in our library10.1016/j.molcel.2005.02.030

  197. 197.

    Weinstock J, Wu J, Cao P, Kingsbury WD, McDermott JL, Kodrasov MP, McKelvey DM, Suresh Kumar KG, Goldenberg SJ, Mattern MR, et al. Selective dual inhibitors of the cancer-related deubiquitylating proteases USP7 and USP47. ACS Medicinal Chemistry Letters. 2012;3:789-792.

    Not in our library10.1021/ml200276j

  198. 198.

    Weissman AM. Themes and variations on ubiquitylation. Nature Reviews. Molecular Cell Biology. 2001;2:169-178.

    Not in our library10.1038/35056563

  199. 199.

    Wen D, Xu Z, Xia L, Liu X, Tu Y, Lei H, Wang W, Wang T, Song L, Ma C, et al. Important role of SUMOylation of Spliceosome factors in prostate cancer cells. Journal of Proteome Research. 2014;13:3571-3582.

    Not in our library10.1021/pr4012848

  200. 200.

    Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, Wu P, Wiesmann C, Baker R, Boone DL, et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling. Nature. 2004;430:694-699.

    Not in our library10.1038/nature02794

  201. 201.

    Wosnitzer MS, Mielnik A, Dabaja A, Robinson B, Schlegel PN, Paduch DA. Ubiquitin specific protease 26 (USP26) expression analysis in human testicular and extragonadal tissues indicates diverse action of USP26 in cell differentiation and tumorigenesis. PLoS ONE. 2014;9:e98638.

    Not in our library10.1371/journal.pone.0098638

  202. 202.
    The Ubiquitin Peptidase UCHL1 Induces G0/G1 Cell Cycle Arrest and Apoptosis Through Stabilizing p53 and Is Frequently Silenced in Breast Cancer · 2012
    No notice
  203. 203.

    Xu M, Takanashi M, Oikawa K, Tanaka M, Nishi H, Isaka K, Kudo M, Kuroda M. USP15 plays an essential role for caspase-3 activation during paclitaxel-induced apoptosis. Biochemical and Biophysical Research Communications. 2009;388:366-371.

    Not in our library10.1016/j.bbrc.2009.08.015

  204. 204.

    Xue S, Jia J. Genetic association between ubiquitin carboxy-terminal hydrolase-L1 gene S18Y polymorphism and sporadic Alzheimer's disease in a Chinese Han population. Brain Research. 2006;1087:28-32.

    Not in our library10.1016/j.brainres.2006.02.121

  205. 205.

    Yamaguchi M, Miyazaki M, Kodrasov MP, Rotinsulu H, Losung F, Mangindaan RE, de Voogd NJ, Yokosawa H, Nicholson B, Tsukamoto S. Spongiacidin C, a pyrrole alkaloid from the marine sponge Stylissa massa, functions as a USP7 inhibitor. Bioorganic & Medicinal Chemistry Letters. 2013;23:3884-3886.

    Not in our library10.1016/j.bmcl.2013.04.066

  206. 206.

    Yamamoto N, Imai J, Watanabe M, Hiroi N, Sugano S, Yoshino G. Restoration of transforming growth factor-β type II receptor reduces tumorigenicity in the human adrenocortical carcinoma SW-13 cell line. Hormone and Metabolic Research. 2006;38:159-166.

    Not in our library10.1055/s-2006-925185

  207. 207.

    Yamazaki T, Hibi K, Takase T, Tezel E, Nakayama H, Kasai Y, Ito K, Akiyama S, Nagasaka T, Nakao A. PGP9.5 as a marker for invasive colorectal cancer. Clinical Cancer Research. 2002;8:192-195.

    Not in our library

  208. 208.

    Yang YA, Yu J. EZH2, an epigenetic driver of prostate cancer. Protein & Cell. 2013;4:331-341.

    Not in our library10.1007/s13238-013-2093-2

  209. 209.

    Yang Y, Hou JQ, Qu LY, Wang GQ, Ju HW, Zhao ZW, Yu ZH, Yang HJ. [Differential expression of USP2, USP14 and UBE4A between ovarian serous cystadenocarcinoma and adjacent normal tissues]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2007;23:504-506.

    Not in our library

  210. 210.

    Yang M, Liu YD, Wang YY, Liu TB, Ge TT, Lou G. Ubiquitin-specific protease 22: a novel molecular biomarker in cervical cancer prognosis and therapeutics. Tumour Biology. 2014;35:929-934.

    Not in our library10.1007/s13277-013-1121-4

  211. 211.

    Yao T, Cohen RE. A cryptic protease couples deubiquitination and degradation by the proteasome. Nature. 2002;419:403-407.

    Not in our library10.1038/nature01071

  212. 212.

    Zarrizi R, Menard J, Belting M, Massoumi R. Deubiquitination of γ-tubulin by BAP1 prevents chromosome instability in breast cancer cells. Cancer Research. 2014;74:6499-6508.

    Not in our library10.1158/0008-5472.can-14-0221

  213. 213.

    Zavacki AM, Arrojo EDR, Freitas BC, Chung M, Harney JW, Egri P, Wittmann G, Fekete C, Gereben B, Bianco AC. The E3 ubiquitin ligase TEB4 mediates degradation of type 2 iodothyronine deiodinase. Molecular and Cellular Biology. 2009;29:5339-5347.

    Not in our library10.1128/mcb.01498-08

  214. 214.

    Zhang Y, Yao L, Zhang X, Ji H, Wang L, Sun S, Pang D. Elevated expression of USP22 in correlation with poor prognosis in patients with invasive breast cancer. Journal of Cancer Research and Clinical Oncology. 2011a;137:1245-1253.

    Not in our library10.1007/s00432-011-0998-9

  215. 215.

    Zhang X, Berger FG, Yang J, Lu X. USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1. EMBO Journal. 2011b;30:2177-2189.

    Not in our library10.1038/emboj.2011.125

  216. 216.

    Zhang L, Zhou F, Drabsch Y, Gao R, Snaar-Jagalska BE, Mickanin C, Huang H, Sheppard KA, Porter JA, Lu CX, et al. USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-β type I receptor. Nature Cell Biology. 2012;14:717-726.

    Not in our library10.1038/ncb2522

  217. 217.

    Zhang J, Cao M, Dong J, Li C, Xu W, Zhan Y, Wang X, Yu M, Ge C, Ge Z, et al. ABRO1 suppresses tumourigenesis and regulates the DNA damage response by stabilizing p53. Nature Communications. 2014;5:5059.

    Not in our library10.1038/ncomms6059

  218. 218.

    Zhong X, Pittman RN. Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates. Human Molecular Genetics. 2006;15:2409-2420.

    Not in our library10.1093/hmg/ddl164

Cited by papers we hold 9

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.