Diverse regulatory manners of human telomerase reverse transcriptase

Abstract

Human telomerase reverse transcriptase (hTERT) is the core subunit of human telomerase and plays important roles in human cancers. Aberrant expression of hTERT is closely associated with tumorigenesis, cancer cell stemness maintaining, cell proliferation, apoptosis inhibition, senescence evasion and metastasis. The molecular basis of hTERT regulation is highly complicated and consists of various layers. A deep and full-scale comprehension of the regulatory mechanisms of hTERT is pivotal in understanding the pathogenesis and searching for therapeutic approaches. In this review, we summarize the recent advances regarding the diverse regulatory mechanisms of hTERT, including the transcriptional (promoter mutation, promoter region methylation and histone acetylation), post-transcriptional (mRNA alternative splicing and non-coding RNAs) and post-translational levels (phosphorylation and ubiquitination), which may provide novel perspectives for further translational diagnosis or therapeutic strategies targeting hTERT.

Hypoxia Predicts Poor Prognosis in Neuroblastoma Patients and Associates with Biological Mechanisms Involved in Telomerase Activation and Tumor Microenvironment Reprogramming

“…The enrichment of various pathways and processes that are involved in telomere maintenance as well as the up-regulation of TERT gene was, in fact, observed in the group of UF NB-hop tumors. The aberrant expression of TERT has been described to be closely associated with tumorigenesis [111], and the activation of telomerase through over-expression of TERT is thought to represent the most common pathway for cellular immortalization [25]. The expression of the TERT gene has been shown to correlate with telomerase activity in experiments involving NB tumor tissues [112] and to be a prognostic marker in various adult and pediatric tumors, including NB, where high levels of telomerase expression/activity were found to predict poor outcome [113,114].…”

TERT—Regulation and Roles in Cancer Formation

“…Sp1-silencing completely inhibits telomerase activity by suppressing TERT expression, leading to apoptosis. Furthermore, mutations in Sp1 binding sites (GC‐boxes) significantly decrease transcriptional activity of TERTp , suggesting that Sp1 protein is involved in TERT transcription ( 100 ). Some reports indicated that cooperation between Sp1 and c-MYC drives cell type-specific TERT expression.…”

“…This is further substantiated by the fact that normal cells have lower levels of Sp1 and c-MYC than cancer cells. However, Sp1 would be a weak candidate for a biomarker of cancer‐specific TERT expression because of its ubiquitous expression in normal cells ( 89 , 100 ).…”

Composition and Function of Telomerase—A Polymerase Associated with the Origin of Eukaryotes

“…It has been proposed that human telomerase is subjected to posttranslational regulation, such as phosphorylation or ubiquitination [126,127], as reviewed in [112]. Putative phosphorylation sites were identified in TERT amino acid sequences from O. sativa [128] or N. tabacum [129], but not in TERT from A. thaliana [128].…”

“…Many studies have dissected the mammalian TERT promoter and identified cis-elements (E-boxes, GC motifs, ETS domain) bound by general transcription factors (TFs), such as c-MYC, NF-κB, STAT3, SP1 or ETS2 ( Figure 4 a) (reviewed in [ 101 , 111 , 112 , 113 ]). Moreover, these general TFs can be regulated by a number of other proteins; e.g., human RuvBL2 (reptin) regulates the c-MYC-dependent transcription of TERT [ 114 ].…”