Abstract
Simple SummaryMaintenance of telomeres is a fundamental step in human carcinogenesis and is primarily regulated by telomerase and the human telomerase reverse transcriptase gene (TERT). Improved understanding of the transcriptional control of this gene may provide potential therapeutic targets. Epigenetic modifications are a prominent mechanism to control telomerase activity and regulation of the TERT gene. TERT-targeting miRNAs have been widely studied and their function explained through pre-clinical in vivo model-based validation studies. Further, histone deacetylase inhibitors are now in pre and early clinical trials with significant clinical success. Importantly, TERT downregulation through epigenetic modifications including TERT promoter methylation, histone deacetylase inhibitors, and miRNA activity might contribute to clinical study design. This review provides an overview of the epigenetic mechanisms involved in the regulation of TERT expression and telomerase activity.Telomerase was first described by Greider and Blackburn in 1984, a discovery ultimately recognized by the Nobel Prize committee in 2009. The three decades following on from its discovery have been accompanied by an increased understanding of the fundamental mechanisms of telomerase activity, and its role in telomere biology. Telomerase has a clearly defined role in telomere length maintenance and an established influence on DNA replication, differentiation, survival, development, apoptosis, tumorigenesis, and a further role in therapeutic resistance in human stem and cancer cells including those of breast and cervical origin. TERT encodes the catalytic subunit and rate-limiting factor for telomerase enzyme activity. The mechanisms of activation or silencing of TERT remain open to debate across somatic, cancer, and stem cells. Promoter mutations upstream of TERT may promote dysregulated telomerase activation in tumour cells but additional factors including epigenetic, transcriptional and posttranscriptional modifications also have a role to play. Previous systematic analysis indicated methylation and mutation of the TERT promoter in 53% and 31%, respectively, of TERT expressing cancer cell lines supporting the concept of a key role for epigenetic alteration associated with TERT dysregulation and cellular transformation. Epigenetic regulators including DNA methylation, histone modification, and non-coding RNAs are now emerging as drivers in the regulation of telomeres and telomerase activity. Epigenetic regulation may be responsible for reversible silencing of TERT in several biological processes including development and differentiation, and increased TERT expression in cancers. Understanding the epigenetic mechanisms behind telomerase regulation holds important prospects for cancer treatment, diagnosis and prognosis. This review will focus on the role of epigenetics in telomerase regulation.
Highlights
Telomerase, a ribonucleoprotein enzyme, is the main complex responsible for telomere elongation
Telomeric Repeat Binding Factors 1 and 2 (TRF1, TRF2), TRF1Interacting Nuclear protein 2 (TIN2), repressor activator protein 1 (RAP1), Protection of Telomeres 1 (POT1) and TPP1 telomere protection protein 1 (TPP1) proteins are necessary for telomere function and form the shelterin complex that protects the telomere structure from DNA damage [25]
Telomerase-positive human tumour cell lines, as well as tumour tissues from a range of organs, demonstrated the same hypermethylation pattern in the region −441 to −218 from the upstream of the transcription start site (UTSS) containing 27 CpG motifs. This indicated that telomerase activity and telomerase reverse transcriptase (TERT) mRNA levels were strongly associated with the methylation pattern of the promoter region [17]
Summary
Telomerase, a ribonucleoprotein enzyme, is the main complex responsible for telomere elongation. Epigenetic modifications through promoter methylation [17], histone acetylation and methylation, transcriptional and posttranscriptional mechanisms, and non-coding RNAs [18] all contribute to the regulation of TERT expression in human tumour cell lines [19,20,21]. Cancer cells can bypass crisis by reactivating telomerase, stabilizing/lengthening telomere ends, and reducing genomic instability levels. They may achieve immortalization via upregulation of telomerase and downregulation of tumour suppressor genes [36]. Aged cells with short telomeres show an increase in both active chromatin marks, H3K4 trimethylation (H3K4me3) and H3K9 acetylation (H3K9ac), across the TERT promoter These results support the concept that telomere length-associated changes or telomere position effect might affect TERT transcription. Human embryonic stem cells (hESCs) have high telomerase activity and long telomeres suggesting that this may be an oversimplification
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