Multiple ETS Factors Participate in the Transcriptional Control of TERT Mutant Promoter in Thyroid Cancers

Simple Summary Mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene are enriched in patients with advanced thyroid tumors. Their consequence is the reactivation of TERT expression through mechanisms that involve specific transcription factors and other signaling inputs. Here, we show that, contrary to what it has been shown in other tumor types, multiple factors of the ETS family are able to control TERT transcription and they do so in both the presence and absence of promoter mutations. We also show that TERT expression is more dependent on the MAPK signaling pathway in thyroid cells without TERT promoter mutations. Our work points to an intricate, still not fully characterized, regulatory network of TERT transcription in thyroid tumors. We caution against the assumption of mechanisms identified in other cancer lineages being identical in TERT-mutant thyroid specimens. Hotspot mutations in the TERT (telomerase reverse transcriptase) gene are key determinants of thyroid cancer progression. TERT promoter mutations (TPM) create de novo consensus binding sites for the ETS ("E26 transformation specific") family of transcription factors. In this study, we systematically knocked down each of the 20 ETS factors expressed in thyroid tumors and screened their effects on TERT expression in seven thyroid cancer cell lines with defined TPM status. We observed that, unlike in other TPM-carrying cancers such as glioblastomas, ETS factor GABPA does not unambiguously regulate transcription from the TERT mutant promoter in thyroid specimens. In fact, multiple members of the ETS family impact TERT expression, and they typically do so in a mutation-independent manner. In addition, we observe that partial inhibition of MAPK, a central pathway in thyroid cancer transformation, is more effective at suppressing TERT transcription in the absence of TPMs. Taken together, our results show a more complex scenario of TERT regulation in thyroid cancers compared with other lineages and suggest that compensatory mechanisms by ETS and other regulators likely exist and advocate for the need for a more comprehensive understanding of the mechanisms of TERT deregulation in thyroid tumors before eventually exploring TPM-specific therapeutic strategies.