Revisiting Telomere Shortening in Cancer

Okamoto, K.; Seimiya, Hiroyuki

doi:10.3390/cells8020107

Cited by 122 publications

(108 citation statements)

References 150 publications

(191 reference statements)

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“…Constitutive activation of the GFR/FGFR-BRAF/RAS pathway leads to constitutive cell growth and division [153]. Mutations in these oncogenes are often detectable in low-grade tumors and probably precede TERTp mutations [22,61,77,112]. The picture is even more clear-cut in HCC, where mutations in β-catenin (CTNNB1) neatly precede TERTp mutations during the process of malignant transformation [62,95,120].…”

Section: Discussionmentioning

confidence: 99%

“…The proliferative advantage conferred by driver mutations in these pathways leads to accelerated telomere erosion. Accordingly, most tumors display telomere dysfunction and shortened telomeres, which leads to chromosome instability [10,22,61,66,98,112,115]. In this scenario, TERT reactivation regenerates telomeres sufficiently to maintain them above the critical threshold and to stabilize the tumor genome [3,18,145].…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, the region between −600 and −200 from the TSS contains a second CTCF binding site and is partially hypermethylated in TERT-expressing cells [41][42][43][44]. The transcriptional control of TERT has been comprehensively reviewed recently [3,4,9,[18][19][20][21][22]29,48] and, as such, is beyond the scope of this review. In this review, we focused on the distribution and exclusiveness of TERTp mutations.…”

Section: Introductionmentioning

confidence: 99%

“…Although TERT activity is regulated principally at the transcriptional level (reviewed in References [3,4,9,[17][18][19][20][21][22]), it may also be regulated through splicing [23,24], post-translational modifications, or intracellular trafficking [25][26][27][28]. The TERT promoter (TERTp) contains binding sites for numerous transcriptional activators including Sp-1, c-Myc, Hypoxia Induced Factor (HIF), AP-2, β-catenin, NF-κB, E-twenty-six (Ets)/ternary complex factors (TCF) family members, and transcriptional repressors (Wilms' tumor (WT1), TP53, Nuclear Transcription Factor, X-Box Binding (NFX-1), Mad-1 and CCCTC binding factor (CTCF)) [3,4,9,[17][18][19][20][21]29].…”

Section: Introductionmentioning

confidence: 99%

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The Solo Play of TERT Promoter Mutations

Hafezi

Perez-Bercoff

2020

Cells

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The reactivation of telomerase reverse transcriptase (TERT) protein is the principal mechanism of telomere maintenance in cancer cells. Mutations in the TERT promoter (TERTp) are a common mechanism of TERT reactivation in many solid cancers, particularly those originating from slow-replicating tissues. They are associated with increased TERT levels, telomere stabilization, and cell immortalization and proliferation. Much effort has been invested in recent years in characterizing their prevalence in different cancers and their potential as biomarkers for tumor stratification, as well as assessing their molecular mechanism of action, but much remains to be understood. Notably, they appear late in cell transformation and are mutually exclusive with each other as well as with other telomere maintenance mechanisms, indicative of overlapping selective advantages and of a strict regulation of TERT expression levels. In this review, we summarized the latest literature on the role and prevalence of TERTp mutations across different cancer types, highlighting their biased distribution. We then discussed the need to maintain TERT levels at sufficient levels to immortalize cells and promote proliferation while remaining within cell sustainability levels. A better understanding of TERT regulation is crucial when considering its use as a possible target in antitumor strategies.Cells 2020, 9, 749 2 of 28 by copy number variants (CNV), TERT or TERTp structural variants, chromosomal rearrangements juxtaposing TERTp to enhancer elements, cellular and viral oncogenes such as Hepatitis B virus (HBV) X protein (HBx) or high-risk Human papillomavirus (HPV)16 and HPV18 E6 oncoprotein, and, last but not least, mutations within TERTp (31% of TERT-expressing cancers) ( Figure 1A) [10, 30-38] (reviewed in [3,4,9,18-20,39]). Increased TERTp methylation is typically recorded in >50% of TERT-expressing tumors and cell lines [10,[40][41][42][43][44][45][46][47]. Epigenetic regulation of TERTp is based on altered methylation patterns of specific regions. Hypomethylation of the region between −200 and −100 from the Translational Start site (TSS), encompassing the core promoter, enables binding of c-Myc and Sp-1, thus reactivating transcription. In contrast, the region spanning exon 1 (positions +1 to ±100 from the TSS) contains a binding site for the DNA insulator CTCF. Hypermethylation of this region disrupts binding of CTCF and therefore allows TERT transcription [41][42][43][44]. Similarly, the region between −600 and −200 from the TSS contains a second CTCF binding site and is partially hypermethylated in TERT-expressing cells [41][42][43][44].

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Solo Play of TERT Promoter Mutations

Hafezi

Perez-Bercoff

2020

Cells

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“…The current concept for biobanks for cancers of mouth/oral origin has been established by the rising demands for access to biological material from large populations, particularly upheld by the evolution of sophisticated high-throughput "-omics" technologies such as parallel DNA sequencing, array techniques and mass spectrometry, which equip detailed and affordable analyses (Okamoto & Seimiya, 2019;Xian, Duleba, Yamamoto, Vincent, & McKeon, 2018).…”

mentioning

confidence: 99%

Need for the biobanking and all‐round “‐omics” approach for cancers of mouth/oral region

et al. 2019

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Cellular senescence in cancer: from mechanisms to detection

Hoffmann

González-López

et al. 2020

Molecular Oncology

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Senescence refers to a cellular state featuring a stable cell-cycle arrest triggered in response to stress. This response also involves other distinct morphological and intracellular changes including alterations in gene expression and epigenetic modifications, elevated macromolecular damage, metabolism deregulation and a complex pro-inflammatory secretory phenotype. The initial demonstration of oncogene-induced senescence in vitro established senescence as an important tumour-suppressive mechanism, in addition to apoptosis. Senescence not only halts the proliferation of premalignant cells but also facilitates the clearance of affected cells through immunosurveillance. Failure to clear senescent cells owing to deficient immunosurveillance may, however, lead to a state of chronic inflammation that nurtures a pro-tumorigenic microenvironment favouring cancer initiation, migration and metastasis. In addition, senescence is a response to post-therapy genotoxic stress. Therefore, tracking the emergence of senescent cells becomes pivotal to detect potential pro-tumorigenic events. Current protocols for the in vivo detection of senescence require the analysis of fixed or deep-frozen tissues, despite a significant clinical need for real-time Abbreviations 5-FU, 5-fluorouracil; AAH, atypical adenomatous hyperplasia, AIS adenocarcinoma in situ; ATM, ataxia-telangiectasia mutated; ATR, ATMand Rad3-related; B2M, b2-microglobulin; BAX, BCL2-associated protein X; BCL-2, B-cell lymphoma 2; BrdU, 5-bromo-2 0-deoxyuridine; C/ EBPb, CCAAT/enhancer-binding protein beta; CCF, cytoplasmic chromatin fragment; CDK, cyclin-dependent kinase; cfDNA, cell-free DNA; cGAS-STING, cyclic GMP-AMP synthase linked to stimulator of interferon genes; CHK, checkpoint kinase; CIS

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Revisiting Telomere Shortening in Cancer

Cited by 122 publications

References 150 publications

The Solo Play of TERT Promoter Mutations

The Solo Play of TERT Promoter Mutations

Need for the biobanking and all‐round “‐omics” approach for cancers of mouth/oral region

Cellular senescence in cancer: from mechanisms to detection

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