Telomerase Reverse Transcriptase (TERT) Regulation in Thyroid Cancer: A Review

Telomerase reverse transcriptase (TERT)is the catalytic subunit of the enzyme telomerase and is essential for telomerase activity. Upregulation ofTERTexpression 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 introduceTERTand telomerase activity as it pertains to thyroid cancer and, highlight the effects ofTERTon cancer cells. We will also explore in detail the differentTERTregulatory strategies and howTERTis reactivated in thyroid cancer cells, specifically. These regulatory mechanisms include both activating single base pairTERTpromoter 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 theTERTpromoter in thyroid cancer cells harboring theTERTpromoter mutation. These entail allele-specific transcriptional activator binding, DNA methylation, histone modifications, and mono-allelic expression ofTERT. Lastly,TERTcopy number alterations and alternative splicing are also implicated. Both amplifications of theTERTlocus and increased full-length transcripts and decreased inactive and dominant negative isoforms result in active telomerase. Finally, the clinical significance ofTERTin thyroid cancer is also reviewed.