Telomerase reverse transcriptase regulates DNMT3B expression/aberrant DNA methylation phenotype and AKT activation in hepatocellular carcinoma

Yu, Jiaqi; Yuan, Xiaotian; Sjöholm, Louise K.; Liu, Tiantian; Kong, Feng; Ekström, Tomas J.; Björkholm, Magnus; Xu, Dawei

doi:10.1016/j.canlet.2018.07.013

Cited by 47 publications

(51 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, a close genomic-epigenetic interaction is required for telomerase activation, like TPE-OLD-mediated TERT transcription. Interestingly, TERT promoter methylation is required for cancer cells to activate TERT transcription, while TERT induction in turn promotes the aberrant methylation by upregulating the expression of DNA methyltransferases, which forms a positive feedback loop [20,23].…”

Section: Discussionmentioning

confidence: 99%

“…Liu et al further demonstrated that TERT served as a partner for the transcription factor Sp1 to facilitate cancer angiogenesis [19]. We recently found that this same mechanism was involved in TERT-mediated aberrant DNA methylation and silencing of tumor suppressor genes in hepatocellular cell carcinoma (HCC) cells [20]. Taken together, TERT or telomerase may contribute to multicancer hallmarks via its telomere lengthening-dependent and independent functions (Fig.…”

Section: Introductionmentioning

confidence: 94%

See 1 more Smart Citation

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

2019

Self Cite

View full text Add to dashboard Cite

Long-lived species Homo sapiens have evolved robust protection mechanisms against cancer by repressing telomerase and maintaining short telomeres, thereby delaying the onset of the majority of cancer types until post-reproductive age. Indeed, telomerase is silent in most differentiated human cells, predominantly due to the transcriptional repression of its catalytic component telomerase reverse transcriptase (TERT) gene. The lack of telomerase/TERT expression leads to progressive telomere erosion in dividing human cells, whereas critically shortened telomere length induces a permanent growth arrest stage named replicative senescence. TERT/telomerase activation has been experimentally shown to be essential to cellular immortalization and malignant transformation by stabilizing telomere length and erasing the senescence barrier. Consistently, TERT expression/telomerase activity is detectable in up to 90% of human primary cancers. Compelling evidence has also accumulated that TERT contributes to cancer development and progression via multiple activities beyond its canonical telomere-lengthening function. Given these key roles of telomerase and TERT in oncogenesis, great efforts have been made to decipher mechanisms underlying telomerase activation and TERT induction. In the last two decades since the TERT gene and promoter were cloned, the derepression of the TERT gene has been shown to be achieved typically at a transcriptional level through dysregulation of oncogenic factors or signaling, post-transcriptional/translational regulation and genomic amplification. However, advances in high-throughput next-generation sequencing technologies have prompted a revolution in cancer genomics, which leads to the recent discovery that genomic alterations take center stage in activating the TERT gene. In this review article, we summarize critical mechanisms activating TERT transcription, with special emphases on the contribution of TERT promoter mutations and structural alterations at the TERT locus, and briefly discuss the underlying implications of these genomic events-driven TERT hyperactivity in cancer initiation/progression and potential clinical applications as well.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Indeed, TERT also contributes to cell survival and proliferation through telomere-independent mechanisms; it facilitates Wnt/β-catenin-dependent [136,137], c-myc-dependent [138,139], and NF-κB-dependent gene transcription [140,141], thereby sustaining both oncogenic signaling pathways and its own transcription in a feedforward loop [29,142]. It also regulates methylation [48,143] and DNA damage responses [144,145], and protects cells from Endoplasmic Reticulum (ER) stress and apoptosis by buffering Reactive Oxygen Species (ROS) and modulating mitochondrial function [145][146][147][148][149][150][151]. It is highly likely that TERT homeostasis is also tuned by these functions within a given tumor type and microenvironment, and by related metabolic alterations that need to be preserved.…”

Section: Exclusiveness Of Tertp Mutationsmentioning

confidence: 99%

The Solo Play of TERT Promoter Mutations

Hafezi

Perez-Bercoff

2020

Cells

View full text Add to dashboard Cite

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].

show abstract

“…DNA hypermethylation is a basic epigenetic modification known to be involved in the regulation of gene expression, mRNA splicing, and genomic stability, and it has been intensively and widely studied in cancer epigenetics . Hypermethylation of the tumor suppressor gene (TSG) promoter region is an important mechanism in several types of cancers, such as colorectal cancer and hepatocellular carcinoma . In recent studies, the potential significance of gene methylation for the diagnosis of LSCC has been evaluated …”

Section: Introductionmentioning

confidence: 99%

“…13 Hypermethylation of the tumor suppressor gene (TSG) promoter region is an important mechanism in several types of cancers, such as colorectal cancer 14 and hepatocellular carcinoma. 15 In recent studies, the potential significance of gene methylation for the diagnosis of LSCC has been evaluated. 16,17 In this study, we assessed the ESRRG promoter methylation status in LSCC by measuring ESRRG promoter methylation in LSCC tissue samples.…”

mentioning

confidence: 99%

ESRRG promoter hypermethylation as a diagnostic and prognostic biomarker in laryngeal squamous cell carcinoma

Shen

Zhou

et al. 2019

Clinical Laboratory Analysis

View full text Add to dashboard Cite

Background Estrogen‐related receptor gamma (ESRRG) has been identified as a tumor suppressor gene in several cancers. We aimed to evaluate ESRRG promoter methylation in laryngeal squamous cell carcinoma (LSCC) and its relative clinical value in LSCC. Methods Bisulfite pyrosequencing assays were performed on 91 pairs of tumor and paracancer tissues from LSCC patients in China. The diagnostic value and overall survival (OS) were analyzed descriptively by receiver operating characteristic (ROC) curves and the Kaplan‐Meier methods, respectively. Results The ESRRG promoter was more frequently hypermethylated in tumor tissues than in adjacent tissues (P < 0.01). ESRRG promoter methylation was significantly increased in advanced T stage tumors (P < 0.01) and advanced clinical stage patients (P < 0.01). Moreover, the area under the ROC curve (AUC) value (0.81) indicated high discrimination accuracy. Furthermore, ESRRG hypermethylation was associated with poor OS, as confirmed by Kaplan‐Meier survival curves (P < 0.01). Conclusion Our study indicated that ESRRG promoter hypermethylation contributed to LSCC‐related risks, primarily tumor progression and survival prognosis, in patients. ESRRG promoter methylation could, therefore, be a diagnostic and prognostic biomarker in LSCC.

show abstract

Telomerase reverse transcriptase regulates DNMT3B expression/aberrant DNA methylation phenotype and AKT activation in hepatocellular carcinoma

Cited by 47 publications

References 47 publications

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

The Solo Play of TERT Promoter Mutations

ESRRG promoter hypermethylation as a diagnostic and prognostic biomarker in laryngeal squamous cell carcinoma

Contact Info

Product

Resources

About