Telomerase and Telomeres Biology in Thyroid Cancer

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.

Keywords: BRD4; EMT; TERT promoter; combined therapies; epigenetic drugs; telomerase; telomeres; thyroid cancer.

Figure 1

Schematic model representing TERT promoter regulation in TCs and some hypotheses of therapeutic interventions. The figure shows the long-range chromatin interaction mediated by GABP factors and BRD4 on the mutated TERT promoter, and all the transcription factors positively influencing TERT expression and for whom we described a possible connection with TERT promoter in TCs. We also summarized the new proposed therapies for aggressive TCs, that may also rely on telomerase inhibition. In particular, MKI that acts on MAPK signaling and epigenetic drugs such as BETi and HDACi that may counteract TERT expression by impairing the function of TFs such as c-Myc and BRD4. Moreover, telomeres deregulation and the subsequent genomic instability, here represented by TERT promoter mutations, may influence the response to immunotherapeutic treatments. Overall, this model shows that there are many possible therapeutic combinations to counteract the aberrant activity of telomerase in TCs and consequently to inhibit one of the major trigger of TC aggressiveness.