Abstract
Telomerase reverse transcriptase (TERT) is the catalytic subunit of the enzyme telomerase and is essential for telomerase activity. Upregulation of TERT expression and resulting telomerase activity occurs in the large majority of malignancies, including thyroid cancer. This upregulation results in continued cellular proliferation and avoidance of cellular senescence and cell death. In this review we will briefly introduce TERT and telomerase activity as it pertains to thyroid cancer and, highlight the effects of TERT on cancer cells. We will also explore in detail the different TERT regulatory strategies and how TERT is reactivated in thyroid cancer cells, specifically. These regulatory mechanisms include both activating single base pair TERT promoter mutations and epigenetic changes at the promoter, including changes in CpG methylation and histone modifications that affect chromatin structure. Further, regulation includes the allele-specific regulation of the TERT promoter in thyroid cancer cells harboring the TERT promoter mutation. These entail allele-specific transcriptional activator binding, DNA methylation, histone modifications, and mono-allelic expression of TERT. Lastly, TERT copy number alterations and alternative splicing are also implicated. Both amplifications of the TERT locus and increased full-length transcripts and decreased inactive and dominant negative isoforms result in active telomerase. Finally, the clinical significance of TERT in thyroid cancer is also reviewed.
Highlights
In contrast to stem cells, non-transformed somatic cells have a limited capacity to divide in tissue culture before cell division ceases
Telomerase reverse transcriptase (TERT) is regulated by a variety of mechanisms, indicative of the complex regulatory effort cells exert to control telomerase activity
Shortened telomeres are found in papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), Hürthle cell carcinoma (HCC), and medullary thyroid cancer (MTC) compared to normal thyroid tissue and benign thyroid nodules [60, 62, 66,67,68]
Summary
In contrast to stem cells, non-transformed somatic cells have a limited capacity to divide in tissue culture before cell division ceases. Cellular senescence results from the progressive shortening of chromosomal ends or telomeres, consisting of identical hexamer repeats, with each cell division This phenomenon is due to the end replication problem, a shortcoming of semiconservative DNA replication, which cannot complete the synthesis of chromosomal ends [2]. TERT activation in cancer occurs through a variety of mechanisms These include activating promoter mutations, alterations in promoter DNA methylation, chromatin remodeling, copy number alterations, and alternative splicing of TERT [9,10,11,12,13]. Activating point mutations in the TERT promoter markedly activate TERT transcription and are associated with epigenetic alterations observed in thyroid cancer cell lines and patient tumors These epigenetic alterations include promoter methylation patterns and histone tail methylation modifications.
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