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

Caitlin E M Thornton,Jingzhu Hao,Prasanna P Tamarapu,Iñigo Landa

doi:10.3390/cancers14020357

Abstract

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.

Highlights

Introduction distributed under the terms andMutations in the proximal promoter of TERT are the first genomic lesions in a gene regulatory region and display a high prevalence across multiple cancer types [1]
Family [25] against the de novo sites created by TERT promoter mutations (TPM) in the gene promoter (50 -CCGGAA-30 ; underlined adenines are created by G > A mutations at TERT-124 and-146)
ETS factors from classes III and IV showed binding preferences (50 -GGA-30 and 50 -GGAT-30, respectively) that likely render them less dependent on de novo sites created by TPMs (Figure 1, top)

Summary

Introduction

Mutations in the proximal promoter of TERT (telomerase reverse transcriptase) are the first genomic lesions in a gene regulatory region and display a high prevalence across multiple cancer types [1] They were first identified in cutaneous melanoma [2,3] and subsequently reported in numerous malignancies [4], including thyroid carcinomas [5,6]. Within each thyroid tumor subtype, TPMs associate with more aggressive features, in combination with constitutive activation of the MAPK (“mitogen-activated protein kinase”) pathway, usually via BRAFV600E driver mutation [8,10,11]. Overall, this stepwise increase in frequency implies that clonal TPMs confer a strong selective advantage as PTC progresses to PDTC/ATC

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Conclusion