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Revisiting Telomere Shortening in Cancer

Keiji Okamoto, Hiroyuki Seimiya

Cells · 2019 · Review · CC BY

doi:10.3390/cells8020107

Abstract

Telomeres, the protective structures of chromosome ends are gradually shortened by each cell division, eventually leading to senescence or apoptosis. Cancer cells maintain the telomere length for unlimited growth by telomerase reactivation or a recombination-based mechanism. Recent genome-wide analyses have unveiled genetic and epigenetic alterations of the telomere maintenance machinery in cancer. While telomerase inhibition reveals that longer telomeres are more advantageous for cell survival, cancer cells often have paradoxically shorter telomeres compared with those found in the normal tissues. In this review, we summarize the latest knowledge about telomere length alterations in cancer and revisit its rationality. Finally, we discuss the potential utility of telomere length as a prognostic biomarker.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 24, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Telomeres are protective structures of chromosome ends containing repetitive DNA sequences (TTAGGG in vertebrates) and associated proteins. In human somatic cells, telomeres are gradually shortened by each cell division by semi-conservative DNA replication, and cells with extremely shortened telomeres reach senescence or apoptosis. However, self-renewing cells, such as embryonic stem cells and most cancer cells, can maintain telomeres to overcome the cell senescence or apoptosis caused by telomere shortening and acquire immortality. Two mechanisms for telomere maintenance have been discovered in previous studies: Transcriptional activation of a telomere reverse transcriptase called telomerase and the activation of alternative lengthening of telomeres (ALT), which is a telomerase-independent telomere maintenance mechanism utilizing the DNA homologous recombination repair pathway. Of all cancer cells, 85–95% expresses telomerase, whereas ~5–15% exhibit ALT pathway activation.

Telomerase consists of two essential components, telomerase RNA (TERC/TR) and telomere reverse transcriptase (TERT), and some accessory proteins, such as DKC1, NHP2, NOP10, pontin/reptin and TCAB1. Telomerase is recruited to single stranded telomeric DNA through interaction with the telomere-localizing protein TPP1. TERT synthesizes telomeric sequences using TERC as a template. In human normal somatic cells, TERC is constitutively expressed, whereas TERT expression is epigenetically silenced. In addition, most cancer cells acquire telomerase activity by re-expressing the limiting factor TERT.

The mechanism for the regulation of TERT transcription has been studied for many years. In 1999, three independent groups isolated the 5’ promoter region of the TERT gene. In the core promoter region, which exists in the proximal 260 base pair upstream from the transcription start sites and is essential for TERT transcription, transcription factors C-MYC and SP1 bind to the E-box (5′-CACGTG-3′) at −165 and +44 bp and five GC boxes (5’-GGGCGG-3′), respectively, to induce TERT mRNA expression. The binding sites for the other transcription factors, such as E2F and AP-1, and an estrogen response element (ERE) for estrogen receptor α binding, have been identified in the promoter region and are involved in TERT transcriptional activation. Another factor related to TERT regulation, CCCTC binding factor (CTCF), which functions as an insulator with cohesion by creating the higher-order chromatin loops across the genome and regulates gene expression both positively and negatively by promoting or blocking enhancer-promoter association in a position-dependent manner, respectively, has also been identified. The phosphatidylinositol-3 kinase (PI3K)/AKT kinase pathway enhances TERT activity at the posttranslational level via TERT phosphorylation by AKT. Thus, TERT expression or activity is regulated at multiple steps by various factors.

Telomeres have two major functions: Genomic sacrifice zones for the end-replication problem (i.e., prevention of loss of genomic information at chromosome ends) and chromosome end protection from DNA damage response. These functions are mainly regulated by the telomere binding protein complex, called shelterin, which is composed of six proteins: TRF1, TRF2, RAP1, TIN2, TPP1 and POT1. Telomere double-stranded DNA (dsDNA) binding protein TRF2 and single-stranded DNA binding protein POT1 are essential proteins for end protection from ATM- and ATR-dependent DNA damage responses and the following DNA repair pathways: Non-homologous end joining and homologous recombination, respectively. TRF2 also protects the telomere ends by regulating the formation of a higher order telomere loop structure called t-loop. The t-loop is formed by the invasion of a single-stranded G-overhang (G-tail, 3’-overhang) at telomere ends into double strand telomeric DNA, which prevents DNA ends from being recognized by the DNA damage response machinery and telomerase. TRF1 has DNA bending activity, which contributes to t-loop formation. Other functions of TRF1 are to promote telomere replication at the S phase of the cell cycle and negatively regulate telomerase through recruitment of TIN2, which tethers TPP1-POT1 heterodimer to single-stranded G-overhang. TPP1-POT1 regulates telomerase activity both positively and negatively. POT1 limits telomerase access to G-overhangs by binding to single-stranded DNA, whereas TPP1 interacts with telomerase to promote telomerase processivity. In addition, cell cycle-dependent phosphorylation of TPP1 is required for the TPP1-TERT interaction.

In this review, we summarize the latest knowledge obtained via whole genome analysis regarding telomere length regulation, mainly focusing on TERT point mutations and the regulatory mechanism of TERT expression. Furthermore, we summarize the rationality for the maintenance of shortened telomeres in cancer and discuss the potential utility of telomere length as a prognostic biomarker.

2. TERT Promoter Mutations in Cancer

Employing advanced genome sequencing technology, two different groups unraveled non-coding mutations in TERT promoter in melanoma. Horn’s group and Huang’s group discovered point mutation in the promoter at −124 (C > T) and −146 base pairs (C > T) from the transcription start site (TSS) (also termed C228T and C250T as these positions are at chromosome 5, 1,295,228 C > T and 1,295,250 C > T, respectively) in sporadic melanoma. Furthermore, Horn et al. discovered a T > G point mutation in the promoter at −57 base pairs from TSS of TERT in familial melanoma. These mutations generate novel consensus binding motifs for E-twenty-six (ETS) transcription factor (GGAA, reverse complement) in the TERT promoter, leading to upregulation of TERT mRNA expression. In ETS family proteins, ETS1 and GA-binding protein transcription factor α (GABPA) and β1 (GABPB1) dimers are specifically recruited to the de novo ETS binding motifs in the TERT promoter, which increases telomerase enzymatic activity and telomere elongation and is correlated with poor prognosis in urothelial cancer. These TERT promoter mutations are currently the most common non-coding somatic mutations in cancer and are present in many types of cancers, including melanoma (67%), glioma (51.1%, specially 83.3% in primary glioblastoma, which is the most common and aggressive type of brain tumor), myxoid liposarcoma (79%), osteosarcoma (4.3%), hepatocellular carcinoma (44%), urothelial carcinoma (50.8%), squamous cell carcinoma (14.4%), medulloblastomas (21%), ovarian clear cell carcinoma (15.9%), thyroid cancer (10%), and bladder cancer (59%).

The percentage of TERT promoter mutation is low in sarcomas except for myxoid liposarcoma because 20 to 65% of sarcoma activates ALT but not telomerase to elongate telomeres. In accordance with this observation, TERT promoter mutations are mutually exclusive with the mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX), death domain associated protein (DAXX) or switch/sucrose non-fermentable (SWI/SNF) related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 1 (SMARCA1), which are chromatin remodeling proteins associated with ALT pathway activation. In addition, ARID1A and PIK3CA mutations also tend to be mutually exclusive with TERT promoter mutations in ovarian clear cell carcinoma or glioma. These proteins regulate telomerase activity epigenetically or post-translationally. SWI/SNF chromatin remodeling protein ARID1A suppresses TERT expression by binding to TSS via the transcriptional repressor SIN3A and accumulates histone H3 lysine 9 trimethylation (H3K9me3). Therefore, ARID1A mutation causes TERT transcription activation. The PIK3CA/AKT/NF-kB pathway activates TERT activity at the protein level via TERT phosphorylation by AKT in breast and ovarian cancers.

In contrast to genes with mutual exclusivity, whole genome sequencing analysis has also revealed a simultaneous gene mutation with TERT promoter mutations. BRAF V600E mutations often co-occur in melanoma and thyroid cancer with TERT point mutations. The BRAF-ERK kinase pathway activates ETS family proteins in melanoma, thyroid cancer and glioma. In melanoma and papillary thyroid carcinoma, ERK activated by mutated BRAF induces direct phosphorylation of ETS1 or phosphorylation of another transcription factor FOS followed by GABPB transcriptional activation. Papillary thyroid carcinoma patients with these double mutations indicate poorer prognosis and reduced survival rates compared with those with single mutations. Thus, the telomere elongation pathway functions dependently or independently of TERT promoter mutations. In some cases, further enhancement of telomerase activity by other gene mutations occurs in the process of tumorigenesis.

3. Epigenetic Regulation of TERT Expression

TERT expression is regulated not only by transcription factors but also by epigenetic status. DNA methylation in the TERT promoter region has been studied for two decades. In contrast to the canonical function of DNA methylation as in gene silencing, it has been reported that methylation levels at the TERT promoter region are correlated with TERT expression levels. DNA methylation levels in the TERT promoter region are altered between specific positions in the region. For example, the position between approximately −600 and −200 bp from TSS is hypermethylated, whereas the area from −200 to +150 bp is relatively methylated at lower levels. Among the low methylation regions, methylation levels at −200 to −100 are reduced compared with the region from +1 to +100 position because the region from −200 to −100 includes E-box and GC box called the core promoter region to which C-MYC and SP1 bind to activate TERT transcription. A CCCTC binding factor (CTCF) binding motif exists in TSS (+1 to +100 region) and also in an enhancer region at approximately 4.5 kb upstream from TSS sites. Whereas the loop structure which connects between enhancer and promoter by recruitment of CTCF in the enhancer region positively regulate TERT mRNA expression, the formation of loop structure at TSS suppresses downstream TERT transcription. Given that recruitment of CTCF is disrupted by DNA methylation, DNA methylation at TSS contributes to promoting TERT mRNA expression. Whole genome sequencing has also demonstrated that TERT expression is positively correlated with methylation levels at the TERT promoter region and is negatively correlated with gene body methylation level.

On the other hand, Stern et al. demonstrated that the methylation level at the −600 position is inversely correlated with TERT transcription. In fact, DNA methylation levels on the TERT promoter are different from each allele because monoallelic TERT promoter mutations occur in some cancer cells. In cancer cells with monoallelic mutations, DNA methylation was present at higher levels in the wild-type allele compared with the mutated allele. Then, the histone methyltransferase for histone H3 lysine 27 trimethylation (H3K27me3), EZH2, is recruited to methylated DNA via polycomb repressive complex 2 (PRC2) to deposit the silencing histone mark exclusively on the wild-type allele. On the other hand, the active histone mark H3K4me2/3 accumulates on the mutated allele of the same promoter region, resulting in TERT expression exclusively from the mutated allele.

GABPA1 recruitment to the TERT promoter via point mutations also contributes to changes in epigenetic histone marks on the promoter region. Akincilar et al. reported that the introduction of TERT promoter mutations at −146C (−146C > T) in colorectal cancer HCT116 cells with the wild-type TERT promoter by CRISPR/Cas9 alters the chromatin status of the TERT promoter to an active conformation. In contrast, restoration of the promoter mutation to the wild-type sequence or depletion of GABPA in melanoma and glioblastoma cell lines enables silencing of the histone mark, suggesting that GABPA binding to TERT promoter is a key step to change the chromatin status. Interestingly, GABPA recruitment to the TERT promoter induces long-range chromosome interaction with a region 300-kb upstream from TERT promoter called T-INT. Long-loop formation occurs in telomeres as well. Telomere position effect-over long distances (TPE-OLD) is another example of transcriptional regulation via the interaction of telomeres with chromosomal regions far from telomeres (see below). TERT is also regulated by this TPE-OLD. In this case, TERT expression is suppressed by loop formation with telomere through the accumulation of silencing chromatin marks. The detailed mechanism is still unknown, but the histone mark on the interacted region might influence the chromatin condition on the other side (telomere is normally silent).

4. Telomere Shortening in Cancer

Although cancers with telomerase activation acquire the ability for telomere elongation, it has been reported that the telomere length of prostate cancers is shorter compared with normal tissues. Recently, Barthel et al. examined telomere length of 18,430 samples across 31 types of cancer cohorts using whole genome sequencing or whole exome sequencing data from The Cancer Genome Atlas (TCGA). They demonstrated that 70% of cohorts exhibit shorter telomeres compared with normal samples and the remaining 30% are regulated by ALT or suspected to be. This finding is also demonstrated by fluorescence in situ hybridization staining of both nevus and melanoma sections.

In the well-established tumorigenesis model, telomeres in human somatic cells gradually become shortened with each cell division. After 50 to 60 cell cycles, cells with shortened telomeres provoke replicative senescence by chromosomal instability and p53 activation, which is induced by the DNA damage response according to telomere shortening. However, some cells that can overcome senescence by the acquisition of genetic mutations in p53 or other checkpoint proteins continue to proliferate; thus, telomeres become critically short, and apoptosis is subsequently induced (crisis). At this point, a minor population of the cells that activate telomerase (or ALT pathway) acquires immortality and proceeds to carcinogenesis.

Chiba et al. examined the ability of TERT point mutants to maintain telomeres through cell division using human embryonic stem (ES) cells. They introduced TERT promoter mutation in ES cells, differentiated these cells into fibroblasts and inactivated checkpoint proteins, such as P53 and CDKN2A. As a result, ES cells with both TERT point mutation and checkpoint inactivation acquired an immortalization phenotype. Of note, despite TERT expression, telomere length was shortened in approximately 70 cell cycles, which is near the crisis phase. Thereafter, TERT expression and telomerase activity emerged for an unknown reason, which stabilized telomere length. Indeed, TERT promoter mutations increase gene expression by only two- to four-fold. In addition, quantification of TERT mRNA copy number revealed that there are less than 5 copies/cell in most telomerase-positive cancers.

Xi et al. also reported that TERT is co-localized only at 5–7% of telomeres by TERT immunofluorescence, in which an amino terminal Flag-SNAP-tag sequence is integrated by CRISPR/Cas9 genome editing. This observation is consistent with previous reports that telomerase prefers to elongate the shortest telomeres. These observations suggest that the extent of TERT expression and telomerase activation immediately after the acquisition of TERT promoter mutations are quite low to elongate all telomeres, and telomerase needs to choose the shortest telomere to elongate, resulting in gradual shortening of bulk telomere length. Then, after telomeres are shortened, TERT activity increases to sufficient levels to stabilize telomere length.

In Saccharomyces cerevisiae, telomerase is activated by extremely shortened telomeres depending on the activation of TEL1, which is a human ataxia telangiectasia mutated (ATM) orthologue. Although it is not known whether this process occurs in human cells, ATM, ataxia telangiectasia and Rad3-related (ATR), and DNA-PK phosphorylate AKT upon induction of the DNA damage response to prompt DNA repair, apoptosis, and cell cycle arrest. Given that TERT is a target of AKT, DNA damage response to telomere shortening might activate Akt, which subsequently phosphorylates TERT and increases telomerase activity.

TERT expression and telomerase activity are regulated by an indirect way as well. TERT gene consists of 16 exons in 42 kb of gene body at chromosome 5p15.33 and 22 splicing variants containing well-examined variants, α- and β-splicing variants, have been identified up to date. None of these variants except for the full length have the enzymatic activity and α-, β- and γ-splicing variants can act as dominant negative variants. α-, β- and γ-splicing variants lack 36 base pairs in exon 6 (α-splicing variant), exons 7 and 8 (β-splicing variant) and exons 11–12 (γ-splicing variant), which exist in the reverse transcriptase domain, respectively. In many types of cancer cells, β-splicing variant is expressed as a major splicing variant. In breast cancer patients with co-expression of the full length and β-splicing variants, the patients with higher β-splicing variant expression showed decreased telomerase activity. Interestingly, during the development of kidney, telomerase activity disappears before the expression of the full-length mRNA is downregulated to undetectable levels and only the splicing variant is left. At this point, splicing variants become dominant against the full length, resulting in suppression of telomerase activity. These observations suggest that the expression of alternatively spliced TERT mRNA regulates the expression level of the full length TERT and regulate telomerase activity.

We also should mention the expression levels of shelterin proteins in cancer. Previous clinical studies have reported that expression levels of shelterin genes, such as TRF1, TRF2, TIN2, and, in some cases, POT1, are elevated in many types of cancer as compared to the noncancerous tissues. Also, it has been reported that TRF1, TRF2 and TIN2 expression levels are correlated with the progression level of cancers. In addition, telomeres in cancer are shorter than those in normal tissues, which is consistent with the next generation sequencing (NGS) data, and cancers with short telomeres show poor prognosis. Interestingly, high expression of these shelterin genes and TERT or even telomerase activity is inversely correlated with telomere length. Considering the shelterin function as a negative regulator of telomerase, it is possible that the increased expression of shelterin proteins restricts telomerase activity, leading to the maintenance of short telomeres, which subsequently contribute to cancer progression.

In the process of tumor development, various mutations are introduced in the cancer cell population, causing intratumor heterogeneity. Recent single cell analyses by NGS have shown that the genetic variance is generated among the cells in a tumor. Huang et al. have reported the increased telomerase activity in the heterogeneous population of T-cells at a single cell level. They showed that upon mitogen stimulation, not all but only a small subpopulation of T-cells reactivate telomerase and preferentially elongate short telomeres. It is possible that there are various cell subpopulations with long to short telomeres during the course of cancer development. Because telomeres become shortened by cell proliferation, only the cells with shortest telomeres may increase telomerase activity to avoid crisis and maintain short telomeres.

5. Potential Advantage of Shortened Telomeres in Cancer

Given that telomerase-mediated telomere elongation is important for the infinite proliferation of TERT-positive cancer cells, genetic or pharmacological inhibition of telomerase activity in cancer cells induces gradual shortening of telomeres and eventual cell senescence or apoptosis. Theoretically, the anticancer effect of telomerase inhibition would emerge earlier in cancer cells with shorter telomeres. In fact, short telomere length could be a predictive biomarker of telomerase inhibitors. Furthermore, a clinical study has indicated that the telomerase inhibitor imetelstat increases median progression-free survival and overall survival in patients with non-small cell lung cancer with short telomeres. These observations suggest that longer telomeres would be more advantageous for cancer cells if telomerase-mediated telomere elongation is abrogated. As described above, however, cancer cells often maintain their telomeres at shorter lengths compared with normal tissues.

As a well-established mechanism for limited telomere elongation, telomere-bound shelterin complexes exert a negative feedback effect on telomerase access to telomeres (so-called “protein-counting” mechanism). TERT transcripts may also inhibit telomerase function because the splicing variants work as dominant negative proteins, as described above. The second interpretation is that the length does not matter if the capping function by t-loop formation is intact. Third, moderate genomic instability elicited by shortened telomeres might be advantageous to cancer evolution. In fact, induction of chromosomal instability via the telomeric DNA damage response followed by end-to-end fusions promotes oncogenic transformation.

We previously addressed whether it is advantageous for cancer cells to maintain short telomeres. First, we identified cancer cell lines that maintained very short telomeres (prostate PC-3, stomach MKN74 and breast HBC-4 cancer cells) and elongated their telomeres by TERT overexpression. Subcutaneous injection of the resulting cells into nude mice led to the formation of xenograft tumors at comparable sizes irrespective of telomere length. Intriguingly, however, the xenografts derived from cancer cells with longer telomeres exhibited more differentiated tissue phenotypes, such as the formation of duct-like structures and the reduced expression of N-cadherin and vimentin, both of which are mesenchymal cell markers and associated with poor prognosis in cancer. Furthermore, although xenograft tumors derived from cancer cells with short telomeres upregulate the expression of type I interferon (IFN) signaling-related genes (Interferon Stimulated Genes, ISGs), tumors from cells with longer telomeres do not upregulate those genes.

ISGs expression is regulated by signal transducer and activator of transcription 1 (STAT1), which is a transcription factor activated by IFN. This IFN/STAT1 pathway exerts an antiviral and antitumor activity by inducing cell cycle arrest or apoptosis, whereas it is also involved in tumor progression. The reason for these two opposite functions of IFN/STAT1 pathway remains elusive but it might be due to the difference of tumor types and genetic background, such as mutations of apoptosis- and cell cycle-related genes. Heterogeneity in the tumor might also affect the cellular response to IFN/STAT1. STAT1 is overexpressed in many types of cancers, including leukemia, breast cancer, squamous cell carcinoma of the head and neck (SCCHN), glioma, renal cell carcinoma, prostate cancer and soft tissue sarcoma. STAT1 overexpression shows resistant to radiation and anticancer drugs and metastasis. Breast cancer cells with high expression of CD44, one of cancer stem cell markers, express higher levels of STAT1 compared with cells with low CD44 expression. One of STAT1-target gene, ISG15, a ubiquitin-like protein, is also involved in the regulation of the expression of stemness-related genes, cell growth, cell migration, and tumorigenicity in pancreatic ductal adenocarcinoma, hepatocellular carcinoma and breast cancers. In accordance with these observations, high expression of STAT1 and its target genes (e.g., ISG15, ITI44, MX1 and OAS1) is associated with lower survival rates in high-grade glioma. In glioblastoma, more than 70% of the cases has the TERT promoter mutation. One of the glioblastoma subtypes, proneural subtype, has features of high expression of platelet derived growth factor receptor alpha (PDGFRA) or isocitrate dehydrogenase 1 (IDH1) gene mutation. WGS analysis showed that IDH1 mutation is mutually exclusive with TERT promoter mutation and partly associated with activation of the ALT pathway. Moreover, the patients of glioblastoma with IDH1 mutation and ALT activation, which is associated with longer telomeres, showed better clinical outcome than those with ALT-negative tumor. Thus, a majority of glioblastoma containing proneural subtype maintains shorter telomeres by TERT promoter mutation although there are some glioblastoma with longer telomeres by ALT activation. Given that alteration of telomere length affects the tissue morphology of the tumors and expression of cancer-associated genes, shortened telomeres might contribute to tumor malignancy through reprograming gene expression signatures.

6. Regulation of Gene Expression by Telomeres

Canonical telomere function involves the protection of chromosome ends and acts as sacrifice sequences for the end replication problem as mentioned above. In addition, telomere length affects the expression of genes adjacent to the telomeric region, which is called the telomere position effect (TPE). TPE was first identified in Saccharomyces cerevisiae by Gottschling et al., who found that expression of RNA polymerase II gene inserted immediately adjacent to telomere locus was suppressed. This phenomenon is caused by silent chromatin conformation of telomeres. Representatives of the genes that are affected by TPE include ISG15 located at human chromosome 1p36.33, which is 1 Mb from telomere and exhibits higher expression in older-aged cells. Robin et al. reported that TPE affects not only genes near telomeres but also those far from telomeres up to 10 Mb by means of long-range loop formation. This atypical TPE is called telomere position effect over long distances (TPE-OLD). Hi-C (chromosome capture followed by high-throughput sequencing) analysis has revealed that some genes, such as DSP (desmoplakin), which is located 7.5 Mb away from telomeres, interact with the subtelomeric region by chromosome loop formation in a telomere length-dependent manner. As another example of TPE-OLD, the shelterin component TRF2 tethers the telomere and interstitial telomere repeats to generate a long-range chromatin loop. These interstitial telomere repeats exist 100-kb downstream of the TERT gene and form a TRF2-dependent chromosome loop with the telomere to suppress TERT gene expression. Given that 2920 interstitial telomere repeat sequences were identified in the human genome by whole genome sequencing, TPE-OLD might affect genome-wide gene expression more broadly than expected. Furthermore, Mukherjee et al. have recently reported telomere length-dependent, genome wide transcriptional regulation by TRF2. TRF2 is enriched at promoter regions of several genes far from telomeres in the cells with shorter telomeres and dissociates from there by telomere elongation. RE-1 silencing transcription factor (REST) and lysine-specific demethylase 1 (LDS1) are recruited to the TRF2-bound promoter regions, resulting in suppression of gene expression by adding the silencing histone marks.

Telomere length-dependent regulation of gene expression may also involve telomeric non-coding RNA called TERRA, which is associated with telomere end protection, maintenance of chromatin structure and telomere length regulation. Telomere elongation by TERT overexpression leads to enhanced TERRA signals, due to the increased number of telomeric tracts in a single TERRA molecule. Thus, enhanced TERRA signals are associated with decreased expression of ISGs in telomere-elongated cancer cells. TERRA-mimicking oligonucleotides repress ISG expression in cancer cells with short telomeres. These observations suggest that cancer cells with longer telomeres upregulate TERRA signals, which subsequently downregulate ISG expression. On the other hand, recent reports have shown that extracellular TERRA included in the exosome vesicles is amplified by telomere stress, and induces inflammatory signaling in recipient cells. Differential behavior of TERRA might be due to where TERRA exists. Secreted TERRA in exosomes may activate inflammation by the activation of Toll-like receptors in the recipient cells whereas intracellular TERRA suppresses an innate immune response, which is activated in the process of tumor formation. Although the functional mediator that binds TERRA and represses ISG expression remains unknown, this phenomenon depends on G-quadruplex formation in TERRA and in TERRA-mimicking oligonucleotides. It is possible that cancer cells may prefer shortened telomeres, wherein TERRA downregulation allows ISG expression for cancer progression.

7. Conclusions and Future Perspectives

Identification of TERT promoter mutations has triggered a remarkable improvement of our understanding of the mechanism for TERT transcriptional activation and the relationship between TERT promoter mutations and other gene mutation to regulate TERT expression and telomere length in a cooperative or mutually exclusive manner. These observations have established the importance of telomere maintenance for carcinogenesis and its malignant progression. Nevertheless, most cancers exhibit shorter telomeres compared with normal tissues despite the risk of crisis, apoptosis or senescence, due to excessive telomere shortening. One rational answer might be that maintaining shortened telomeres causes activation of specific genes, such as ISGs, which are required for cancer progression (Figure 1).

Accumulating evidence has demonstrated that short telomeres correlate with increased cancer malignancy, and telomere length in cancer would be useful as a prognostic biomarker or a risk predictor. Some reports have shown the association of telomere length with a poor prognosis of cancer by monitoring telomere length in blood cell DNA as a surrogate biomarker. Furthermore, exosome-derived DNA or circulating cell-free DNA (cfDNA) might be more useful to examine the utility of telomere length as a biomarker because cancer-derived DNA exists in those samples. For example, Wan et al. reported the association of telomere length measured by using circulating serum DNA with the risk of hepatocellular carcinoma in hepatitis B virus patients. Meanwhile, it has been also reported that length of the telomeric G-tail (3′-overhang) instead of telomere length, is a better biomarker for predictions of disease risk. TERRA also might become a useful biomarker because it is included in exosomes as above mentioned. Further investigations will reveal the relationship between telomere length and gene expression regulated by telomeres and tumor progression in more detail, and a deeper understanding of telomere length as a biomarker will ensure its utility in cancer precision medicine and prevention.

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    Kimura A., Ohmichi M., Kawagoe J., Kyo S., Mabuchi S., Takahashi T., Ohshima C., Arimoto-Ishida E., Nishio Y., Inoue M., et al. Induction of hTERT expression and phosphorylation by estrogen via Akt cascade in human ovarian cancer cell lines. Oncogene. 2004;23:4505-4515.

    Not in our library10.1038/sj.onc.1207582

  20. 20.

    de Lange T. Shelterin: The protein complex that shapes and safeguards human telomeres. Genes Dev. 2005;19:2100-2110.

    Not in our library10.1101/gad.1346005

  21. 21.

    Denchi E.L., de Lange T. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature. 2007;448:1068-1071.

    Not in our library10.1038/nature06065

  22. 22.

    Okamoto K., Bartocci C., Ouzounov I., Diedrich J.K., Yates J.R., Denchi E.L. A two-step mechanism for TRF2-mediated chromosome-end protection. Nature. 2013;494:502-505.

    Not in our library10.1038/nature11873

  23. 23.

    He H., Multani A.S., Cosme-Blanco W., Tahara H., Ma J., Pathak S., Deng Y., Chang S. POT1b protects telomeres from end-to-end chromosomal fusions and aberrant homologous recombination. Embo J. 2006;25:5180-5190.

    Not in our library10.1038/sj.emboj.7601294

  24. 24.

    Hockemeyer D., Daniels J.P., Takai H., de Lange T. Recent expansion of the telomeric complex in rodents: Two distinct POT1 proteins protect mouse telomeres. Cell. 2006;126:63-77.

    Not in our library10.1016/j.cell.2006.04.044

  25. 25.

    Wu L., Multani A.S., He H., Cosme-Blanco W., Deng Y., Deng J.M., Bachilo O., Pathak S., Tahara H., Bailey S.M., et al. Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres. Cell. 2006;126:49-62.

    Not in our library10.1016/j.cell.2006.05.037

  26. 26.

    Van Ly D., Low R.R.J., Frolich S., Bartolec T.K., Kafer G.R., Pickett H.A., Gaus K., Cesare A.J. Telomere Loop Dynamics in Chromosome End Protection. Mol. Cell. 2018;71:510-525.

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

  27. 27.

    Doksani Y., Wu J.Y., de Lange T., Zhuang X. Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation. Cell. 2013;155:345-356.

    Not in our library10.1016/j.cell.2013.09.048

  28. 28.

    Griffith J.D., Comeau L., Rosenfield S., Stansel R.M., Bianchi A., Moss H., de Lange T. Mammalian telomeres end in a large duplex loop. Cell. 1999;97:503-514.

    Not in our library10.1016/s0092-8674(00)80760-6

  29. 29.

    Stansel R.M., de Lange T., Griffith J.D. T-loop assembly in vitro involves binding of TRF2 near the 3′ telomeric overhang. Embo J. 2001;20:5532-5540.

    Not in our library10.1093/emboj/20.19.5532

  30. 30.

    Bianchi A., Smith S., Chong L., Elias P., de Lange T. TRF1 is a dimer and bends telomeric DNA. Embo J. 1997;16:1785-1794.

    Not in our library10.1093/emboj/16.7.1785

  31. 31.

    Sfeir A., Kosiyatrakul S.T., Hockemeyer D., MacRae S.L., Karlseder J., Schildkraut C.L., de Lange T. Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell. 2009;138:90-103.

    Not in our library10.1016/j.cell.2009.06.021

  32. 32.

    Ye J.Z., Hockemeyer D., Krutchinsky A.N., Loayza D., Hooper S.M., Chait B.T., de Lange T. POT1-interacting protein PIP1: A telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev. 2004;18:1649-1654.

    Not in our library10.1101/gad.1215404

  33. 33.

    Liu D., Safari A., O’Connor M.S., Chan D.W., Laegeler A., Qin J., Songyang Z. PTOP interacts with POT1 and regulates its localization to telomeres. Nat. Cell Biol. 2004;6:673-680.

    Not in our library10.1038/ncb1142

  34. 34.

    Houghtaling B.R., Cuttonaro L., Chang W., Smith S. A dynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2. Curr. Biol. 2004;14:1621-1631.

    Not in our library10.1016/j.cub.2004.08.052

  35. 35.

    Okamoto K., Iwano T., Tachibana M., Shinkai Y. Distinct roles of TRF1 in the regulation of telomere structure and lengthening. J. Biol. Chem. 2008;283:23981-23988.

    Not in our library10.1074/jbc.m802395200

  36. 36.

    Kelleher C., Kurth I., Lingner J. Human protection of telomeres 1 (POT1) is a negative regulator of telomerase activity in vitro. Mol. Cell. Biol. 2005;25:808-818.

    Not in our library10.1128/mcb.25.2.808-818.2005

  37. 37.

    Nandakumar J., Bell C.F., Weidenfeld I., Zaug A.J., Leinwand L.A., Cech T.R. The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature. 2012;492:285-289.

    Not in our library10.1038/nature11648

  38. 38.

    Zhang Y., Chen L.Y., Han X., Xie W., Kim H., Yang D., Liu D., Songyang Z. Phosphorylation of TPP1 regulates cell cycle-dependent telomerase recruitment. Proc. Natl. Acad. Sci. USA. 2013;110:5457-5462.

    Not in our library10.1073/pnas.1217733110

  39. 39.

    Hirai Y., Tamura M., Otani J., Ishikawa F. NEK6-mediated phosphorylation of human TPP1 regulates telomere length through telomerase recruitment. Genes Cells. 2016;21:874-889.

    Not in our library10.1111/gtc.12391

  40. 40.

    Horn S., Figl A., Rachakonda P.S., Fischer C., Sucker A., Gast A., Kadel S., Moll I., Nagore E., Hemminki K., et al. TERT promoter mutations in familial and sporadic melanoma. Science. 2013;339:959-961.

    Not in our library10.1126/science.1230062

  41. 41.

    Huang F.W., Hodis E., Xu M.J., Kryukov G.V., Chin L., Garraway L.A. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013;339:957-959.

    Not in our library10.1126/science.1229259

  42. 42.

    Bell R.J., Rube H.T., Kreig A., Mancini A., Fouse S.D., Nagarajan R.P., Choi S., Hong C., He D., Pekmezci M., et al. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science. 2015;348:1036-1039.

    Not in our library10.1126/science.aab0015

  43. 43.

    Borah S., Xi L., Zaug A.J., Powell N.M., Dancik G.M., Cohen S.B., Costello J.C., Theodorescu D., Cech T.R. Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer. Science. 2015;347:1006-1010.

    Not in our library10.1126/science.1260200

  44. 44.

    Killela P.J., Reitman Z.J., Jiao Y., Bettegowda C., Agrawal N., Diaz L.A., Friedman A.H., Friedman H., Gallia G.L., Giovanella B.C., et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc. Natl. Acad. Sci. USA. 2013;110:6021-6026.

    Not in our library10.1073/pnas.1303607110

  45. 45.

    Vinagre J., Almeida A., Populo H., Batista R., Lyra J., Pinto V., Coelho R., Celestino R., Prazeres H., Lima L., et al. Frequency of TERT promoter mutations in human cancers. Nat. Commun. 2013;4:2185.

    Not in our library10.1038/ncomms3185

  46. 46.

    Nault J.C., Mallet M., Pilati C., Calderaro J., Bioulac-Sage P., Laurent C., Laurent A., Cherqui D., Balabaud C., Zucman-Rossi J. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat. Commun. 2013;4:2218.

    Not in our library10.1038/ncomms3218

  47. 47.

    Koelsche C., Renner M., Hartmann W., Brandt R., Lehner B., Waldburger N., Alldinger I., Schmitt T., Egerer G., Penzel R., et al. TERT promoter hotspot mutations are recurrent in myxoid liposarcomas but rare in other soft tissue sarcoma entities. J. Exp. Clin. Cancer Res. 2014;33:33.

    Not in our library10.1186/1756-9966-33-33

  48. 48.

    Henson J.D., Reddel R.R. Assaying and investigating Alternative Lengthening of Telomeres activity in human cells and cancers. FEBS Lett. 2010;584:3800-3811.

    Not in our library10.1016/j.febslet.2010.06.009

  49. 49.

    Heaphy C.M., de Wilde R.F., Jiao Y., Klein A.P., Edil B.H., Shi C., Bettegowda C., Rodriguez F.J., Eberhart C.G., Hebbar S., et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science. 2011;333:425.

    Not in our library10.1126/science.1207313

  50. 50.

    Schwartzentruber J., Korshunov A., Liu X.Y., Jones D.T., Pfaff E., Jacob K., Sturm D., Fontebasso A.M., Quang D.A., Tonjes M., et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482:226-231.

    Not in our library10.1038/nature10833

  51. 51.

    Flynn R.L., Cox K.E., Jeitany M., Wakimoto H., Bryll A.R., Ganem N.J., Bersani F., Pineda J.R., Suva M.L., Benes C.H., et al. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science. 2015;347:273-277.

    Not in our library10.1126/science.1257216

  52. 52.
    The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma · 2018
    No notice
  53. 53.

    Wu R.C., Ayhan A., Maeda D., Kim K.R., Clarke B.A., Shaw P., Chui M.H., Rosen B., Shih Ie M., Wang T.L. Frequent somatic mutations of the telomerase reverse transcriptase promoter in ovarian clear cell carcinoma but not in other major types of gynaecological malignancy. J. Pathol. 2014;232:473-481.

    Not in our library10.1002/path.4315

  54. 54.

    Williams E.A., Miller J.J., Tummala S.S., Penson T., Iafrate A.J., Juratli T.A., Cahill D.P. TERT promoter wild-type glioblastomas show distinct clinical features and frequent PI3K pathway mutations. Acta Neuropathol. Commun. 2018;6:106.

    Not in our library10.1186/s40478-018-0613-2

  55. 55.

    Suryo Rahmanto Y., Jung J.G., Wu R.C., Kobayashi Y., Heaphy C.M., Meeker A.K., Wang T.L., Shih Ie M. Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells. J. Biol. Chem. 2016;291:9690-9699.

    Not in our library10.1074/jbc.m115.707612

  56. 56.

    Rusinek D., Pfeifer A., Krajewska J., Oczko-Wojciechowska M., Handkiewicz-Junak D., Pawlaczek A., Zebracka-Gala J., Kowalska M., Cyplinska R., Zembala-Nozynska E., et al. Coexistence of TERT Promoter Mutations and the BRAF V600E Alteration and Its Impact on Histopathological Features of Papillary Thyroid Carcinoma in a Selected Series of Polish Patients. Int. J. Mol. Sci. 2018;19.

    Not in our library10.3390/ijms19092647

  57. 57.

    Hipskind R.A., Buscher D., Nordheim A., Baccarini M. Ras/MAP kinase-dependent and -independent signaling pathways target distinct ternary complex factors. Genes Dev. 1994;8:1803-1816.

    Not in our library10.1101/gad.8.15.1803

  58. 58.

    Whitmarsh A.J., Shore P., Sharrocks A.D., Davis R.J. Integration of MAP kinase signal transduction pathways at the serum response element. Science. 1995;269:403-407.

    Not in our library10.1126/science.7618106

  59. 59.

    Vallarelli A.F., Rachakonda P.S., Andre J., Heidenreich B., Riffaud L., Bensussan A., Kumar R., Dumaz N. TERT promoter mutations in melanoma render TERT expression dependent on MAPK pathway activation. Oncotarget. 2016;7:53127-53136.

    Not in our library10.18632/oncotarget.10634

  60. 60.
    Regulation of mutant TERT by BRAF V600E/MAP kinase pathway through FOS/GABP in human cancer · 2018
    No notice
  61. 61.

    Devereux T.R., Horikawa I., Anna C.H., Annab L.A., Afshari C.A., Barrett J.C. DNA methylation analysis of the promoter region of the human telomerase reverse transcriptase (hTERT) gene. Cancer Res. 1999;59:6087-6090.

    Not in our library

  62. 62.

    Shin K.H., Kang M.K., Dicterow E., Park N.H. Hypermethylation of the hTERT promoter inhibits the expression of telomerase activity in normal oral fibroblasts and senescent normal oral keratinocytes. Br. J. Cancer. 2003;89:1473-1478.

    Not in our library10.1038/sj.bjc.6601291

  63. 63.

    Dessain S.K., Yu H., Reddel R.R., Beijersbergen R.L., Weinberg R.A. Methylation of the human telomerase gene CpG island. Cancer Res. 2000;60:537-541.

    Not in our library

  64. 64.

    Zinn R.L., Pruitt K., Eguchi S., Baylin S.B., Herman J.G. hTERT is expressed in cancer cell lines despite promoter DNA methylation by preservation of unmethylated DNA and active chromatin around the transcription start site. Cancer Res. 2007;67:194-201.

    Not in our library10.1158/0008-5472.can-06-3396

  65. 65.

    Stern J.L., Paucek R.D., Huang F.W., Ghandi M., Nwumeh R., Costello J.C., Cech T.R. Allele-Specific DNA Methylation and Its Interplay with Repressive Histone Marks at Promoter-Mutant TERT Genes. Cell Rep. 2017;21:3700-3707.

    Not in our library10.1016/j.celrep.2017.12.001

  66. 66.

    Barthel F.P., Wei W., Tang M., Martinez-Ledesma E., Hu X., Amin S.B., Akdemir K.C., Seth S., Song X., Wang Q., et al. Systematic analysis of telomere length and somatic alterations in 31 cancer types. Nature Genet. 2017;49:349-357.

    Not in our library10.1038/ng.3781

  67. 67.

    Stern J.L., Theodorescu D., Vogelstein B., Papadopoulos N., Cech T.R. Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers. Genes Dev. 2015;29:2219-2224.

    Not in our library10.1101/gad.269498.115

  68. 68.

    Huang F.W., Bielski C.M., Rinne M.L., Hahn W.C., Sellers W.R., Stegmeier F., Garraway L.A., Kryukov G.V. TERT promoter mutations and monoallelic activation of TERT in cancer. Oncogenesis. 2015;4:e176.

    Not in our library10.1038/oncsis.2015.39

  69. 69.

    Akincilar S.C., Khattar E., Boon P.L., Unal B., Fullwood M.J., Tergaonkar V. Long-range chromatin interactions drive mutant TERT promoter activation. Cancer Discov. 2016;6:1276-1291.

    Not in our library10.1158/2159-8290.cd-16-0177

  70. 70.

    Robin J.D., Ludlow A.T., Batten K., Magdinier F., Stadler G., Wagner K.R., Shay J.W., Wright W.E. Telomere position effect: Regulation of gene expression with progressive telomere shortening over long distances. Genes Dev. 2014;28:2464-2476.

    Not in our library10.1101/gad.251041.114

  71. 71.
    Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer · 2016
    No notice
  72. 72.

    Garcia-Cao M., O’Sullivan R., Peters A.H., Jenuwein T., Blasco M.A. Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat. Genet. 2004;36:94-99.

    Not in our library10.1038/ng1278

  73. 73.

    Sommerfeld H.J., Meeker A.K., Piatyszek M.A., Bova G.S., Shay J.W., Coffey D.S. Telomerase activity: A prevalent marker of malignant human prostate tissue. Cancer Res. 1996;56:218-222.

    Not in our library

  74. 74.

    Meeker A.K., Hicks J.L., Platz E.A., March G.E., Bennett C.J., Delannoy M.J., De Marzo A.M. Telomere shortening is an early somatic DNA alteration in human prostate tumorigenesis. Cancer Res. 2002;62:6405-6409.

    Not in our library

  75. 75.

    Chiba K., Lorbeer F.K., Shain A.H., McSwiggen D.T., Schruf E., Oh A., Ryu J., Darzacq X., Bastian B.C., Hockemeyer D. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science. 2017;357:1416-1420.

    Not in our library10.1126/science.aao0535

  76. 76.

    Hayflick L. THE LIMITED IN VITRO LIFETIME OF HUMAN DIPLOID CELL STRAINS. Exp. Cell Res. 1965;37:614-636.

    Not in our library10.1016/0014-4827(65)90211-9

  77. 77.

    Wright W.E., Brasiskyte D., Piatyszek M.A., Shay J.W. Experimental elongation of telomeres extends the lifespan of immortal x normal cell hybrids. Embo J. 1996;15:1734-1741.

    Not in our library10.1002/j.1460-2075.1996.tb00519.x

  78. 78.

    Vaziri H., West M.D., Allsopp R.C., Davison T.S., Wu Y.S., Arrowsmith C.H., Poirier G.G., Benchimol S. ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post-translational activation of p53 protein involving poly(ADP-ribose) polymerase. Embo J. 1997;16:6018-6033.

    Not in our library10.1093/emboj/16.19.6018

  79. 79.

    Chin L., Artandi S.E., Shen Q., Tam A., Lee S.L., Gottlieb G.J., Greider C.W., DePinho R.A. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell. 1999;97:527-538.

    Not in our library10.1016/s0092-8674(00)80762-x

  80. 80.

    Preto A., Singhrao S.K., Haughton M.F., Kipling D., Wynford-Thomas D., Jones C.J. Telomere erosion triggers growth arrest but not cell death in human cancer cells retaining wild-type p53: Implications for antitelomerase therapy. Oncogene. 2004;23:4136-4145.

    Not in our library10.1038/sj.onc.1207564

  81. 81.
    Cancer-associated TERT promoter mutations abrogate telomerase silencing · 2015
    No notice
  82. 82.

    Yi X., Shay J.W., Wright W.E. Quantitation of telomerase components and hTERT mRNA splicing patterns in immortal human cells. Nucleic Acids Res. 2001;29:4818-4825.

    Not in our library10.1093/nar/29.23.4818

  83. 83.

    Xi L., Schmidt J.C., Zaug A.J., Ascarrunz D.R., Cech T.R. A novel two-step genome editing strategy with CRISPR-Cas9 provides new insights into telomerase action and TERT gene expression. Genome Biol. 2015;16:231.

    Not in our library10.1186/s13059-015-0791-1

  84. 84.

    Hemann M.T., Strong M.A., Hao L.Y., Greider C.W. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell. 2001;107:67-77.

    Not in our library10.1016/s0092-8674(01)00504-9

  85. 85.

    Ouellette M.M., Liao M., Herbert B.S., Johnson M., Holt S.E., Liss H.S., Shay J.W., Wright W.E. Subsenescent telomere lengths in fibroblasts immortalized by limiting amounts of telomerase. J. Biol. Chem. 2000;275:10072-10076.

    Not in our library10.1074/jbc.275.14.10072

  86. 86.

    Samper E., Flores J.M., Blasco M.A. Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc-/- mice with short telomeres. EMBO Rep. 2001;2:800-807.

    Not in our library10.1093/embo-reports/kve174

  87. 87.

    Chang M., Arneric M., Lingner J. Telomerase repeat addition processivity is increased at critically short telomeres in a Tel1-dependent manner in Saccharomyces cerevisiae. Genes Dev. 2007;21:2485-2494.

    Not in our library10.1101/gad.1588807

  88. 88.

    Liu Q., Turner K.M., Alfred Yung W.K., Chen K., Zhang W. Role of AKT signaling in DNA repair and clinical response to cancer therapy. Neuro-Oncol. 2014;16:1313-1323.

    Not in our library10.1093/neuonc/nou058

  89. 89.

    Hrdlickova R., Nehyba J., Bose H.R. Alternatively spliced telomerase reverse transcriptase variants lacking telomerase activity stimulate cell proliferation. Mol. Cell. Biol. 2012;32:4283-4296.

    Not in our library10.1128/mcb.00550-12

  90. 90.

    Wong M.S., Wright W.E., Shay J.W. Alternative splicing regulation of telomerase: A new paradigm? Trends Genet. 2014;30:430-438.

    Not in our library10.1016/j.tig.2014.07.006

  91. 91.

    Colgin L.M., Wilkinson C., Englezou A., Kilian A., Robinson M.O., Reddel R.R. The hTERTalpha splice variant is a dominant negative inhibitor of telomerase activity. Neoplasia. 2000;2:426-432.

    Not in our library10.1038/sj.neo.7900112

  92. 92.

    Lincz L.F., Mudge L.M., Scorgie F.E., Sakoff J.A., Hamilton C.S., Seldon M. Quantification of hTERT splice variants in melanoma by SYBR green real-time polymerase chain reaction indicates a negative regulatory role for the beta deletion variant. Neoplasia. 2008;10:1131-1137.

    Not in our library10.1593/neo.08644

  93. 93.

    Liu X., Wang Y., Chang G., Wang F., Wang F., Geng X. Alternative Splicing of hTERT Pre-mRNA: A Potential Strategy for the Regulation of Telomerase Activity. Int. J. Mol. Sci. 2017;18.

    Not in our library10.3390/ijms18030567

  94. 94.

    Saeboe-Larssen S., Fossberg E., Gaudernack G. Characterization of novel alternative splicing sites in human telomerase reverse transcriptase (hTERT): Analysis of expression and mutual correlation in mRNA isoforms from normal and tumour tissues. BMC Mol. Biol. 2006;7:26.

    Not in our library10.1186/1471-2199-7-26

  95. 95.

    Rha S.Y., Jeung H.C., Park K.H., Kim J.J., Chung H.C. Changes of telomerase activity by alternative splicing of full-length and beta variants of hTERT in breast cancer patients. Oncol. Res. 2009;18:213-220.

    Not in our library10.3727/096504009x12596189659123

  96. 96.

    Ulaner G.A., Hu J.F., Vu T.H., Giudice L.C., Hoffman A.R. Tissue-specific alternate splicing of human telomerase reverse transcriptase (hTERT) influences telomere lengths during human development. Int. J. Cancer. 2001;91:644-649.

    Not in our library10.1002/1097-0215(200002)9999:9999<::aid-ijc1103>3.0.co;2-v

  97. 97.

    Ulaner G.A., Hu J.F., Vu T.H., Giudice L.C., Hoffman A.R. Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts. Cancer Res. 1998;58:4168-4172.

    Not in our library

  98. 98.

    Ozden S., Tiber P.M., Ozgen Z., Ozyurt H., Serakinci N., Orun O. Expression of TRF2 and its prognostic relevance in advanced stage cervical cancer patients. Biol. Res. 2014;47:61.

    Not in our library10.1186/0717-6287-47-61

  99. 99.

    Panero J., Stanganelli C., Arbelbide J., Fantl D.B., Kohan D., Garcia Rivello H., Rabinovich G.A., Slavutsky I. Expression profile of shelterin components in plasma cell disorders. Clinical significance of POT1 overexpression. Blood Cells Mol. Dis. 2014;52:134-139.

    Not in our library10.1016/j.bcmd.2013.10.002

  100. 100.

    Chen W., Wang Y., Li F., Lin W., Liang Y., Ma Z. Expression of Telomere Repeat Binding Factor 1 and TRF2 in Prostate Cancer and Correlation with Clinical Parameters. BioMed. Res. Int. 2017;2017:9764752.

    Not in our library10.1155/2017/9764752

  101. 101.

    Hu H., Zhang Y., Zou M., Yang S., Liang X.Q. Expression of TRF1, TRF2, TIN2, TERT, KU70, and BRCA1 proteins is associated with telomere shortening and may contribute to multistage carcinogenesis of gastric cancer. J. Cancer Res. Clin. Oncol. 2010;136:1407-1414.

    Not in our library10.1007/s00432-010-0795-x

  102. 102.

    Oh B.K., Kim Y.J., Park C., Park Y.N. Up-regulation of telomere-binding proteins, TRF1, TRF2, and TIN2 is related to telomere shortening during human multistep hepatocarcinogenesis. Am. J. Pathol. 2005;166:73-80.

    Not in our library10.1016/s0002-9440(10)62233-x

  103. 103.

    Gay-Bellile M., Romero P., Cayre A., Veronese L., Privat M., Singh S., Combes P., Kwiatkowski F., Abrial C., Bignon Y.J., et al. ERCC1 and telomere status in breast tumours treated with neoadjuvant chemotherapy and their association with patient prognosis. J. Pathol. Clin. Res. 2016;2:234-246.

    Not in our library10.1002/cjp2.52

  104. 104.

    Butler K.S., Hines W.C., Heaphy C.M., Griffith J.K. Coordinate regulation between expression levels of telomere-binding proteins and telomere length in breast carcinomas. Cancer Med. 2012;1:165-175.

    Not in our library10.1002/cam4.14

  105. 105.

    De Bie J., Demeyer S., Alberti-Servera L., Geerdens E., Segers H., Broux M., De Keersmaecker K., Michaux L., Vandenberghe P., Voet T., et al. Single-cell sequencing reveals the origin and the order of mutation acquisition in T-cell acute lymphoblastic leukemia. Leukemia. 2018;32:1358-1369.

    Not in our library10.1038/s41375-018-0127-8

  106. 106.

    Liu M., Liu Y., Di J., Su Z., Yang H., Jiang B., Wang Z., Zhuang M., Bai F., Su X. Multi-region and single-cell sequencing reveal variable genomic heterogeneity in rectal cancer. BMC Cancer. 2017;17:787.

    Not in our library10.1186/s12885-017-3777-4

  107. 107.

    Winterhoff B.J., Maile M., Mitra A.K., Sebe A., Bazzaro M., Geller M.A., Abrahante J.E., Klein M., Hellweg R., Mullany S.A., et al. Single cell sequencing reveals heterogeneity within ovarian cancer epithelium and cancer associated stromal cells. Gynecologic Oncol. 2017;144:598-606.

    Not in our library10.1016/j.ygyno.2017.01.015

  108. 108.

    Huang E.E., Tedone E., O’Hara R., Cornelius C., Lai T.P., Ludlow A., Wright W.E., Shay J.W. The maintenance of telomere length in CD28+ T cells during T lymphocyte stimulation. Sci. Rep. 2017;7:6785.

    Not in our library10.1038/s41598-017-05174-7

  109. 109.

    Hahn W.C., Stewart S.A., Brooks M.W., York S.G., Eaton E., Kurachi A., Beijersbergen R.L., Knoll J.H., Meyerson M., Weinberg R.A. Inhibition of telomerase limits the growth of human cancer cells. Nat. Med. 1999;5:1164-1170.

    Not in our library10.1038/13495

  110. 110.

    Seimiya H., Muramatsu Y., Ohishi T., Tsuruo T. Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics. Cancer Cell. 2005;7:25-37.

    Not in our library10.1016/j.ccr.2004.11.021

  111. 111.

    Seimiya H., Oh-hara T., Suzuki T., Naasani I., Shimazaki T., Tsuchiya K., Tsuruo T. Telomere shortening and growth inhibition of human cancer cells by novel synthetic telomerase inhibitors MST-312, MST-295, and MST-1991. Mol. Cancer Ther. 2002;1:657-665.

    Not in our library

  112. 112.

    Frink R.E., Peyton M., Schiller J.H., Gazdar A.F., Shay J.W., Minna J.D. Telomerase inhibitor imetelstat has preclinical activity across the spectrum of non-small cell lung cancer oncogenotypes in a telomere length dependent manner. Oncotarget. 2016;7:31639-31651.

    Not in our library10.18632/oncotarget.9335

  113. 113.

    Fujiwara C., Muramatsu Y., Nishii M., Tokunaka K., Tahara H., Ueno M., Yamori T., Sugimoto Y., Seimiya H. Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells. Sci. Rep. 2018;8:14827.

    Not in our library10.1038/s41598-018-33139-x

  114. 114.

    Chiappori A.A., Kolevska T., Spigel D.R., Hager S., Rarick M., Gadgeel S., Blais N., Von Pawel J., Hart L., Reck M., et al. A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. Ann. Oncol. 2015;26:354-362.

    Not in our library10.1093/annonc/mdu550

  115. 115.

    Shore D., Bianchi A. Telomere length regulation: Coupling DNA end processing to feedback regulation of telomerase. Embo J. 2009;28:2309-2322.

    Not in our library10.1038/emboj.2009.195

  116. 116.

    Marcand S., Gilson E., Shore D. A protein-counting mechanism for telomere length regulation in yeast. Science. 1997;275:986-990.

    Not in our library10.1126/science.275.5302.986

  117. 117.

    Artandi S.E., Chang S., Lee S.L., Alson S., Gottlieb G.J., Chin L., DePinho R.A. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature. 2000;406:641-645.

    Not in our library10.1038/35020592

  118. 118.

    Hirashima K., Migita T., Sato S., Muramatsu Y., Ishikawa Y., Seimiya H. Telomere length influences cancer cell differentiation in vivo. Mol. Cell. Biol. 2013;33:2988-2995.

    Not in our library10.1128/mcb.00136-13

  119. 119.

    Derycke L.D., Bracke M.E. N-cadherin in the spotlight of cell-cell adhesion, differentiation, embryogenesis, invasion and signalling. Int. J. Dev. Biol. 2004;48:463-476.

    Not in our library10.1387/ijdb.041793ld

  120. 120.

    Ivashkiv L.B., Donlin L.T. Regulation of type I interferon responses. Nat. Rev. Immunol. 2014;14:36-49.

    Not in our library10.1038/nri3581

  121. 121.

    Chin Y.E., Kitagawa M., Su W.C., You Z.H., Iwamoto Y., Fu X.Y. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Science. 1996;272:719-722.

    Not in our library10.1126/science.272.5262.719

  122. 122.

    Bromberg J.F., Horvath C.M., Wen Z., Schreiber R.D., Darnell J.E. Transcriptionally active STAT1 is required for the antiproliferative effects of both interferon alpha and interferon gamma. Proc. Natl. Acad. Sci. USA. 1996;93:7673-7678.

    Not in our library10.1073/pnas.93.15.7673

  123. 123.

    Buettner R., Mora L.B., Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin. Cancer Res. 2002;8:945-954.

    Not in our library

  124. 124.

    Greenwood C., Metodieva G., Al-Janabi K., Lausen B., Alldridge L., Leng L., Bucala R., Fernandez N., Metodiev M.V. Stat1 and CD74 overexpression is co-dependent and linked to increased invasion and lymph node metastasis in triple-negative breast cancer. J. Proteom. 2012;75:3031-3040.

    Not in our library10.1016/j.jprot.2011.11.033

  125. 125.

    Zhu H., Wang Z., Xu Q., Zhang Y., Zhai Y., Bai J., Liu M., Hui Z., Xu N. Inhibition of STAT1 sensitizes renal cell carcinoma cells to radiotherapy and chemotherapy. Cancer Biol. Therapy. 2012;13:401-407.

    Not in our library10.4161/cbt.19291

  126. 126.

    Tsai M.H., Cook J.A., Chandramouli G.V., DeGraff W., Yan H., Zhao S., Coleman C.N., Mitchell J.B., Chuang E.Y. Gene expression profiling of breast, prostate, and glioma cells following single versus fractionated doses of radiation. Cancer Res. 2007;67:3845-3852.

    Not in our library10.1158/0008-5472.can-06-4250

  127. 127.

    Khodarev N.N., Beckett M., Labay E., Darga T., Roizman B., Weichselbaum R.R. STAT1 is overexpressed in tumors selected for radioresistance and confers protection from radiation in transduced sensitive cells. Proc. Natl. Acad. Sci. USA. 2004;101:1714-1719.

    Not in our library10.1073/pnas.0308102100

  128. 128.
    Identification of genes associated with platinum drug sensitivity and resistance in human ovarian cancer cells · 2005
    No notice
  129. 129.

    Fryknas M., Dhar S., Oberg F., Rickardson L., Rydaker M., Goransson H., Gustafsson M., Pettersson U., Nygren P., Larsson R., et al. STAT1 signaling is associated with acquired crossresistance to doxorubicin and radiation in myeloma cell lines. Int. J. Cancer. 2007;120:189-195.

    Not in our library10.1002/ijc.22291

  130. 130.

    Rickardson L., Fryknas M., Dhar S., Lovborg H., Gullbo J., Rydaker M., Nygren P., Gustafsson M.G., Larsson R., Isaksson A. Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles. Br. J. Cancer. 2005;93:483-492.

    Not in our library10.1038/sj.bjc.6602699

  131. 131.

    Khodarev N.N., Roach P., Pitroda S.P., Golden D.W., Bhayani M., Shao M.Y., Darga T.E., Beveridge M.G., Sood R.F., Sutton H.G., et al. STAT1 pathway mediates amplification of metastatic potential and resistance to therapy. PLoS ONE. 2009;4:e5821.

    Not in our library10.1371/journal.pone.0005821

  132. 132.

    Weichselbaum R.R., Ishwaran H., Yoon T., Nuyten D.S., Baker S.W., Khodarev N., Su A.W., Shaikh A.Y., Roach P., Kreike B., et al. An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer. Proc. Natl. Acad. Sci. USA. 2008;105:18490-18495.

    Not in our library10.1073/pnas.0809242105

  133. 133.

    Qadir A.S., Ceppi P., Brockway S., Law C., Mu L., Khodarev N.N., Kim J., Zhao J.C., Putzbach W., Murmann A.E., et al. CD95/Fas increases stemness in cancer cells by inducing a STAT1-dependent type I interferon response. Cell Rep. 2017;18:2373-2386.

    Not in our library10.1016/j.celrep.2017.02.037

  134. 134.

    Sainz B., Martin B., Tatari M., Heeschen C., Guerra S. ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells. Cancer Res. 2014;74:7309-7320.

    Not in our library10.1158/0008-5472.can-14-1354

  135. 135.

    Li C., Wang J., Zhang H., Zhu M., Chen F., Hu Y., Liu H., Zhu H. Interferon-stimulated gene 15 (ISG15) is a trigger for tumorigenesis and metastasis of hepatocellular carcinoma. Oncotarget. 2014;5:8429-8441.

    Not in our library10.18632/oncotarget.2316

  136. 136.

    Forys J.T., Kuzmicki C.E., Saporita A.J., Winkeler C.L., Maggi L.B., Weber J.D. ARF and p53 coordinate tumor suppression of an oncogenic IFN-beta-STAT1-ISG15 signaling axis. Cell Rep. 2014;7:514-526.

    Not in our library10.1016/j.celrep.2014.03.026

  137. 137.
    Expression Signature of IFN/STAT1 Signaling Genes Predicts Poor Survival Outcome in Glioblastoma Multiforme in a Subtype-Specific Manner · 2012
    No notice
  138. 138.

    Verhaak R.G., Hoadley K.A., Purdom E., Wang V., Qi Y., Wilkerson M.D., Miller C.R., Ding L., Golub T., Mesirov J.P., et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98-110.

    Not in our library10.1016/j.ccr.2009.12.020

  139. 139.

    Eckel-Passow J.E., Lachance D.H., Molinaro A.M., Walsh K.M., Decker P.A., Sicotte H., Pekmezci M., Rice T., Kosel M.L., Smirnov I.V., et al. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. N. Engl. J. Med. 2015;372:2499-2508.

    Not in our library10.1056/nejmoa1407279

  140. 140.

    Nonoguchi N., Ohta T., Oh J.E., Kim Y.H., Kleihues P., Ohgaki H. TERT promoter mutations in primary and secondary glioblastomas. Acta Neuropathol. 2013;126:931-937.

    Not in our library10.1007/s00401-013-1163-0

  141. 141.

    Sturm D., Bender S., Jones D.T., Lichter P., Grill J., Becher O., Hawkins C., Majewski J., Jones C., Costello J.F., et al. Paediatric and adult glioblastoma: Multiform (epi)genomic culprits emerge. Nat. Rev. Cancer. 2014;14:92-107.

    Not in our library10.1038/nrc3655

  142. 142.

    McDonald K.L., McDonnell J., Muntoni A., Henson J.D., Hegi M.E., von Deimling A., Wheeler H.R., Cook R.J., Biggs M.T., Little N.S., et al. Presence of alternative lengthening of telomeres mechanism in patients with glioblastoma identifies a less aggressive tumor type with longer survival. J. Neuropathol. Exp. Neurol. 2010;69:729-736.

    Not in our library10.1097/nen.0b013e3181e576cf

  143. 143.

    Gottschling D.E., Aparicio O.M., Billington B.L., Zakian V.A. Position effect at S. cerevisiae telomeres: Reversible repression of Pol II transcription. Cell. 1990;63:751-762.

    Not in our library10.1016/0092-8674(90)90141-z

  144. 144.

    Lou Z., Wei J., Riethman H., Baur J.A., Voglauer R., Shay J.W., Wright W.E. Telomere length regulates ISG15 expression in human cells. Aging. 2009;1:608-621.

    Not in our library10.18632/aging.100066

  145. 145.

    Mukherjee A.K., Sharma S., Sengupta S., Saha D., Kumar P., Hussain T., Srivastava V., Roy S.D., Shay J.W., Chowdhury S. Telomere length-dependent transcription and epigenetic modifications in promoters remote from telomere ends. PLos Genet. 2018;14:e1007782.

    Not in our library10.1371/journal.pgen.1007782

  146. 146.
    TERRA recruitment of polycomb to telomeres is essential for histone trymethylation marks at telomeric heterochromatin · 2018
    No notice
  147. 147.

    Porro A., Feuerhahn S., Lingner J. TERRA-reinforced association of LSD1 with MRE11 promotes processing of uncapped telomeres. Cell Rep. 2014;6:765-776.

    Not in our library10.1016/j.celrep.2014.01.022

  148. 148.

    Deng Z., Norseen J., Wiedmer A., Riethman H., Lieberman P.M. TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres. Mol. Cell. 2009;35:403-413.

    Not in our library10.1016/j.molcel.2009.06.025

  149. 149.

    Deng Z., Wang Z., Stong N., Plasschaert R., Moczan A., Chen H.S., Hu S., Wikramasinghe P., Davuluri R.V., Bartolomei M.S., et al. A role for CTCF and cohesin in subtelomere chromatin organization, TERRA transcription, and telomere end protection. Embo J. 2012;31:4165-4178.

    Not in our library10.1038/emboj.2012.266

  150. 150.

    Redon S., Zemp I., Lingner J. A three-state model for the regulation of telomerase by TERRA and hnRNPA1. Nucleic Acids Res. 2013;41:9117-9128.

    Not in our library10.1093/nar/gkt695

  151. 151.

    Hirashima K., Seimiya H. Telomeric repeat-containing RNA/G-quadruplex-forming sequences cause genome-wide alteration of gene expression in human cancer cells in vivo. Nucleic Acids Res. 2015;43:2022-2032.

    Not in our library10.1093/nar/gkv063

  152. 152.

    Wang Z., Deng Z., Dahmane N., Tsai K., Wang P., Williams D.R., Kossenkov A.V., Showe L.C., Zhang R., Huang Q., et al. Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes. Proc. Natl. Acad. Sci. USA. 2015;112:E6293-E6300.

    Not in our library10.1073/pnas.1505962112

  153. 153.

    Wang Z., Lieberman P.M. The crosstalk of telomere dysfunction and inflammation through cell-free TERRA containing exosomes. RNA Biol. 2016;13:690-695.

    Not in our library10.1080/15476286.2016.1203503

  154. 154.

    Arons E., Zhou H., Edelman D.C., Gomez A., Steinberg S.M., Petersen D., Wang Y., Meltzer P.S., Kreitman R.J. Impact of telomere length on survival in classic and variant hairy cell leukemia. Leuk. Res. 2015;39:1360-1366.

    Not in our library10.1016/j.leukres.2015.09.015

  155. 155.

    Weischer M., Nordestgaard B.G., Cawthon R.M., Freiberg J.J., Tybjaerg-Hansen A., Bojesen S.E. Short telomere length, cancer survival, and cancer risk in 47,102 individuals. J. Natl. Cancer Inst. 2013;105:459-468.

    Not in our library10.1093/jnci/djt016

  156. 156.

    Seow W.J., Cawthon R.M., Purdue M.P., Hu W., Gao Y.T., Huang W.Y., Weinstein S.J., Ji B.T., Virtamo J., Hosgood H.D., et al. Telomere length in white blood cell DNA and lung cancer: A pooled analysis of three prospective cohorts. Cancer Res. 2014;74:4090-4098.

    Not in our library10.1158/0008-5472.can-14-0459

  157. 157.

    Wan S., Hann H.W., Ye Z., Hann R.S., Lai Y., Wang C., Li L., Myers R.E., Li B., Xing J., et al. Prospective and longitudinal evaluations of telomere length of circulating DNA as a risk predictor of hepatocellular carcinoma in HBV patients. Carcinogenesis. 2017;38:439-446.

    Not in our library10.1093/carcin/bgx021

  158. 158.
    Telomere G-tail Length is a Promising Biomarker Related to White Matter Lesions and Endothelial Dysfunction in Patients With Cardiovascular Risk: A Cross-sectional Study · 2015
    Not checked
  159. 159.

    Seimiya H. Predicting risk at the end of the end: Telomere G-tail as a biomarker. eBioMedicine. 2015;2:804-805.

    Not in our library10.1016/j.ebiom.2015.07.006

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