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

Telomere length maintenance, critical for cancer progression, can be driven by TERT promoter mutations (TERTp (MUT) ), 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 TERTp (MUT) activity by inserting a luciferase reporter downstream of TERTp (MUT) 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 TERTp (MUT) and wild-type promoters are governed by these pathways, distinct factors mediate each mechanism. Specifically, AURKB, via REST, is recruited to TERTp (MUT) by TRIM28. These findings highlight TRIM28 as a promising therapeutic target for TERTp (MUT) -driven thyroid cancers.