AURKB and PI3K/AKT/mTOR pathways converge to regulate TERT expression

Telomere length maintenance, critical for cancer progression, can be driven by <i>TERT</i> promoter mutations (<i>TERTp</i> ^<i>MUT</i> ), which are markers of poor prognosis across multiple cancers. Their tumor-specificity also makes them attractive chemotherapeutic targets. Here, we identified previously uncharacterized pathways regulating <i>TERTp</i> ^<i>MUT</i> activity by inserting a luciferase reporter downstream of <i>TERTp</i> ^<i>MUT</i> in SW1736 anaplastic thyroid cancer cells via CRISPR-Cas9, generating SW1736^TERT/LUC, and screening a 218-kinase inhibitor library. Beyond MAPK regulation, we found co-regulatory roles for PI3K/AKT/mTOR1 signaling and the cell cycle via Aurora kinase B (AURKB). Further analyses using quantitative PCR, immunoprecipitation (IP), and chromatin IP in thyroid cell models revealed that although both <i>TERTp</i> ^<i>MUT</i> and wild-type promoters are governed by these pathways, distinct factors mediate each mechanism. Specifically, AURKB, via REST, is recruited to <i>TERTp</i> ^<i>MUT</i> by TRIM28. These findings highlight TRIM28 as a promising therapeutic target for <i>TERTp</i> ^<i>MUT</i> -driven thyroid cancers.