CDK12-Mediated Phosphorylation of FOXA1 Promotes Prostate Cancer Progression via the MDM2-p53 Axis.

ABSTRACT: Prostate cancer (PCa) progression is driven by intricate molecular mechanisms involving dysregulated signaling networks and posttranslational modifications of key regulatory proteins. In this study, we identify a novel oncogenic pathway wherein cyclin-dependent kinase 12 (CDK12) physically interacts with and phosphorylates forkhead box A1 (FOXA1) at serine 234 (S234). Phosphorylation at this residue markedly enhances FOXA1 transcriptional activity, leading to up-regulation of downstream targets including murine double minute 2 (MDM2), a critical negative regulator of the p53 tumor suppressor. Mechanistically, this CDK12-FOXA1-MDM2 axis destabilizes p53, attenuates apoptotic signaling, and promotes PCa cell survival and proliferation. Therapeutic targeting of CDK12 using the small-molecule

SUBMITTER: Yan B 

PROVIDER: S-EPMC12696697 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature