Abstract
Telomere and telomerase regulation contributes to the onset and evolution of several tumors, including highly aggressive thyroid cancers (TCs). TCs are the most common endocrine malignancies and are generally characterized by a high rate of curability. However, a small but significant percentage develops distant metastasis or progresses into undifferentiated forms associated with bad prognosis and for which poor therapeutic options are available. Mutations in telomerase reverse transcriptase (TERT) promoter are among the most credited prognostic marker of aggressiveness in TCs. Indeed, their frequency progressively increases passing from indolent lesions to aggressive and anaplastic forms. TERT promoter mutations create binding sites for transcription factors, increasing TERT expression and telomerase activity. Furthermore, aggressiveness of TCs is associated with TERT locus amplification. These data encourage investigating telomerase regulating pathways as relevant drivers of TC development and progression to foster the identification of new therapeutics targets. Here, we summarize the current knowledge about telomere regulation and TCs, exploring both canonical and less conventional pathways. We discuss the possible role of telomere homeostasis in mediating response to cancer therapies and the possibility of using epigenetic drugs to re-evaluate the use of telomerase inhibitors. Combined treatments could be of support to currently used therapies still presenting weaknesses.
Highlights
Telomere protection and/or elongation are considered among the primary mechanisms of cancer survival and aggressiveness
BET inhibitors (BETi), which we previously described as a potential therapeutic options for aggressive thyroid cancers (TCs) harboring telomerase reverse transcriptase (TERT) promoter mutations, have been shown to drastically suppress c-Myc expression, and this effect has been widely documented in human patients in several clinical studies for solid and hematological tumors [41,42]
Mutations in TERT promoter are among the more common genetic abnormalities observed in cancers and the most frequent alterations observed in aggressive thyroid tumors
Summary
Telomere protection and/or elongation are considered among the primary mechanisms of cancer survival and aggressiveness. Among the mechanisms leading to aberrant telomerase activation, TERT promoter mutations C228T and C250T (−124 bp and −146 bp upstream of TERT’s transcription starting site, respectively) are frequent in cancer and associated with increased aggressiveness and metastatic potential in several tumor settings. These alterations cause the formation of ectopic binding sites for specific transcription factors (TFs) within the TERT promoter inducing its overexpression [7]. We aim to summarize the current knowledge about telomere regulation in TC, with a particular focus on highly aggressive lesions and with the intent to discuss the potential application of these observations for defining both new prognostic tools and new potential targets to improve patient management
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