Abstract
Embryonic stem cells and induced pluripotent stem cells have the ability to maintain their telomere length via expression of an enzymatic complex called telomerase. Similarly, more than 85%–90% of cancer cells are found to upregulate the expression of telomerase, conferring them with the potential to proliferate indefinitely. Telomerase Reverse Transcriptase (TERT), the catalytic subunit of telomerase holoenzyme, is the rate-limiting factor in reconstituting telomerase activity in vivo. To date, the expression and function of the human Telomerase Reverse Transcriptase (hTERT) gene are known to be regulated at various molecular levels (including genetic, mRNA, protein and subcellular localization) by a number of diverse factors. Among these means of regulation, transcription modulation is the most important, as evident in its tight regulation in cancer cell survival as well as pluripotent stem cell maintenance and differentiation. Here, we discuss how hTERT gene transcription is regulated, mainly focusing on the contribution of trans-acting factors such as transcription factors and epigenetic modifiers, as well as genetic alterations in hTERT proximal promoter.
Highlights
The ends of human chromosomes are capped by telomeres which protect the chromosome termini from degradation, end-to-end fusion and recombination [1,2]
Despite the strong evidences brought forth by the various studies above regarding the key role c-Myc plays in the modulation of human Telomerase Reverse Transcriptase (hTERT) expression and telomerase activity, several studies involving the use of primary tumor samples have proven the lack of correlation between c-Myc expression and hTERT mRNA levels, in hepatocellular carcinoma and breast carcinoma tissue samples [208,209]
In several renal carcinoma cell lines tested, HIF-2α overexpression led to an increase in hTERT promoter activity and its depletion resulted in lower hTERT mRNA levels [134]
Summary
The ends of human chromosomes are capped by telomeres which protect the chromosome termini from degradation, end-to-end fusion and recombination [1,2]. Mutations in telomerase and telomere maintenance genes have been found in patients with telomeropathies [20,21,22], which results in decreased telomerase activity and accelerated telomere shortening. These genes control telomerase ribonucleoprotein maturation, assembly, recruitment, and engagement, revealing their importance in telomere length homeostasis. Recent studies have revealed the potential role of promoter mutations and chromosomal rearrangements in the activation of telomerase in cancer cells. These results have provided potential new strategies in targeting telomerase for cancer therapy. We summarize the recent advances in the understanding of the transcriptional regulation of hTERT gene, focusing our attention on trans-acting factors, namely transcription factors and epigenetic modifiers, as well as genetic alterations in hTERT proximal region
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