TERT biology and function in cancer: beyond immortalisation

Abstract

Evasion of replicative senescence and proliferation without restriction, sometimes designated as immortalisation, is one of the hallmarks of cancer that may be attained through reactivation of telomerase in somatic cells. In contrast to most normal cells in which there is lack of telomerase activity, upregulation of TERT transcription/activity is detected in 80-90% of malignant tumours. In several types of cancer, there is a relationship between the presence of TERT promoter mutations, TERT mRNA expression and clinicopathological features, but the biological bridge between the occurrence of TERT promoter mutations and the aggressive/invasive features displayed by the tumours remains unidentified. We and others have associated the presence of TERT promoter mutations with metastisation/survival in several types of cancer. In follicular cell-derived thyroid cancer, such mutations are associated with worse prognostic features (age of patients, tumour size and tumour stage) as well as with distant metastases, worse response to treatment and poorer survival. In this review, we analyse the data reported in several studies that imply TERT transcription reactivation/activity with cell proliferation, tumour invasion and metastisation. A particular attention is given to the putative connections between TERT transcriptional reactivation and signalling pathways frequently altered in cancer, such as c-MYC, NF-κB and B-Catenin.

Transcriptome analysis of papillary thyroid cancer harboring telomerase reverse transcriptase promoter mutation

“…Telomere shortening induces a transcriptional response involving genes relevant to some metabolic pathways. 12 Proteomics analysis of ectopic TERT expression in cancer cells revealed an overexpression of mitochondrial proteins, glycolytic enzymes, ribosome-related proteins, and epithelial-tomesenchymal transition markers. 42 In this regard, we did observe an upregulation of some glycolytic markers, such as ENO2 (enolase 2) and SLC16A1 (monocarboxylic acid transporter 1 or MCT1).…”

“…Recent evidence indicates that TERT may play a role in cellular biology other than telomere maintenance. 12 A prevalent cytoplasmic TERT staining was observed in malignant thyroid tumors, whereas normal tissues had both cytoplasmic and nuclear TERT immunoreactivities. 13 The different subcellular localization of TERT in thyroid cancer suggests that TERT participates in other tumorigenesis-promoting activities that take place in the cytoplasm.…”

“…Recent evidence indicates that TERT may play a role in cellular biology other than telomere maintenance . A prevalent cytoplasmic TERT staining was observed in malignant thyroid tumors, whereas normal tissues had both cytoplasmic and nuclear TERT immunoreactivities .…”

The Solo Play of TERT Promoter Mutations

“…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]. The transcriptional control of TERT has been comprehensively reviewed recently [3,4,9,[18][19][20][21][22]29,48] and, as such, is beyond the scope of this review. In this review, we focused on the distribution and exclusiveness of TERTp mutations.…”

“…Although TERT activity is regulated principally at the transcriptional level (reviewed in References [3,4,9,[17][18][19][20][21][22]), it may also be regulated through splicing [23,24], post-translational modifications, or intracellular trafficking [25][26][27][28]. The TERT promoter (TERTp) contains binding sites for numerous transcriptional activators including Sp-1, c-Myc, Hypoxia Induced Factor (HIF), AP-2, β-catenin, NF-κB, E-twenty-six (Ets)/ternary complex factors (TCF) family members, and transcriptional repressors (Wilms' tumor (WT1), TP53, Nuclear Transcription Factor, X-Box Binding (NFX-1), Mad-1 and CCCTC binding factor (CTCF)) [3,4,9,[17][18][19][20][21]29]. TERT expression can be reactivated reactivated 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][31][32][33][34][35][36][37][38] (reviewed in [3,4,9,[18]…”