Human telomerase reverse transcriptase regulation by DNA methylation, transcription factor binding and alternative splicing (Review)

Abstract

The catalytic subunit of telomerase, human telomerase reverse transcriptase (hTERT), plays an essential role in telomere maintenance to oppose cellular senescence and, is highly regulated in normal and cancerous cells. Regulation of hTERT occurs through multiple avenues, including a unique pattern of CpG promoter methylation and alternative splicing. Promoter methylation affects the binding of transcription factors, resulting in changes in expression of the gene. In addition to expression level changes, changes in promoter binding can affect alternative splicing in a cotranscriptional manner. The alternative splicing of hTERT results in either the full length transcript which can form the active telomerase complex with hTR, or numerous inactive isoforms. Both regulation strategies are exploited in cancer to activate telomerase, however, the exact mechanism is unknown. Therefore, unraveling the link between promoter methylation status and alternative splicing for hTERT could expose yet another level of hTERT regulation. In an attempt to provide insight into the cellular control of active telomerase in cancer, this review will discuss our current perspective on CpG methylation of the hTERT promoter region, summarize the different forms of alternatively spliced variants, and examine examples of transcription factor binding that affects splicing.

Characterization of human telomerase reverse transcriptase promoter methylation and transcription factor binding in differentiated thyroid cancer cell lines

“…Our characterization of the TERT promoter by bisulfite amplicon sequencing revealed that DTC cell lines exhibit the dual‐methylation pattern commonly observed in other telomerase positive cancer cell types, including medullary thyroid cancer, that is, low levels of methylation in the minimal promoter near the TSS, while the region further upstream was highly methylated. This upstream region of hypermethylation has been shown to be tightly correlated with TERT expression, activation of telomerase, and worse clinical outcomes, and is used as a biomarker in pediatric brain tumors and melanoma, specifically with methylation of the region 1 295 647 to 703 serving as a prognostic marker for tumor progression and poor prognosis .…”

“…The upstream promoter region, covering 1 295 587 to 1 295 800, was partially or fully methylated at every CpG in all DTC cell lines. As this area has been shown to be characteristically highly methylated in other cancers, epiallele analysis was conducted to examine this area further. While in Figure , the upstream region of normal thyroid tissue appears partially methylated, epiallele analysis displays the region being mostly unmethylated.…”

Epigenetic perturbation driving asleep telomerase reverse transcriptase: Possible therapeutic avenues in carcinoma

“…[3][4][5][6][7][8][12][13][14][15] In recent times, interests are rising to dissect out the contribution of DNA methylation, histone methylation, histone acetylation, and also non-coding RNAs in the epigenetically facilitated expression of hTERT. [25][26][27][28][31][32][33]44 Telomerase activity was detected in more than 95% of advanced stage breast cancers. It was absent in 19%-32% of less advanced cancers.…”

“…75,88 Clinical relevance of epigenetic regulation of TERT In recent times, numerous reports are available to support several molecular inhibitors and phytochemical agents that block epigenetic modifiers such as DNMTs and HDACs, and as a consequence, the activity and expression of TERT are blocked. [25][26][27][28][29][30][31][32][33][89][90][91][92] In spite of several in vitro and in vivo studies pinpointing the concomitant use of several epigenetic inhibitors and telomerase inhibitors, the success is awaited in the form of clinical trial attempts and outcomes. However, certain clinical success in the form of small-molecule inhibitor drugs targeting DNA methylation (e.g.…”

Aberrant expression of ETS1 and ETS2 proteins in cancer

“…Human telomerase reverse transcriptase gene ( TERT ) encodes a rate-limiting catalytic subunit of telomerase essential for genomic integrity (11, 32–34 for reviews). TERT expression is repressed in somatic cells except for self-renewing proliferative cells and tumor cells (32).…”