Translation initiation is orchestrated by the cap binding and 43S preinitiation complexes (PIC). Eukaryotic initiation factor 1A (EIF1A) is essential for recruitment of the ternary complex and for assembling the 43S PIC. Recurrent EIF1AX mutations in papillary thyroid cancers are mutually exclusive with other drivers, including RAS . EIF1AX mutations are enriched in advanced thyroid cancers, where they display a striking co-occurrence with RAS , which cooperates to induce tumorigenesis in mice and isogenic cell lines. The C-terminal EIF1AX-A113splice mutation is the most prevalent in advanced thyroid cancer. EIF1AX-A113splice variants stabilize the PIC and induce ATF4, a sensor of cellular stress, which is co-opted to suppress EIF2α phosphorylation, enabling a general increase in protein synthesis. RAS stabilizes c-MYC, an effect augmented by EIF1AX-A113splice. ATF4 and c-MYC induce expression of amino acid transporters and enhance sensitivity of mTOR to amino acid supply. These mutually reinforcing events generate therapeutic vulnerabilities to MEK, BRD4, and mTOR kinase inhibitors.
SIGNIFICANCE:Mutations of EIF1AX, a component of the translation PIC, co-occur with RAS in advanced thyroid cancers and promote tumorigenesis. EIF1AX-A113splice drives an ATF4-induced dephosphorylation of EIF2α, resulting in increased protein synthesis. ATF4 also cooperates with c-MYC to sensitize mTOR to amino acid supply, thus generating vulnerability to mTOR kinase inhibitors.EIF1AX is an essential subunit of the translation PIC (10, 12). We performed coimmunoprecipitation (co-IP) experiments to probe for possible aberrant interactions of EIF1AX mutants with components of the TC and the PIC. IP of Research.on July 10, 2020.
Mutations of subunits of the SWI/SNF chromatin remodeling complexes occur commonly in cancers of different lineages, including advanced thyroid cancers. Here we show that thyroidspecific loss of Arid1a, Arid2 or Smarcb1 in mouse Braf V600E -mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. As compared to normal thyrocytes, Braf V600E -mutant mouse PTCs have decreased lineage transcription factor expression and accessibility to their target DNA
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.
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