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

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 inhibitor THZ531 or RNA interference effectively abrogates FOXA1 phosphorylation, restores p53 stability, reactivates apoptotic pathways, and suppresses tumor growth. Notably, the identification of S234 as a functional phosphorylation site in FOXA1 reveals a previously uncharacterized posttranslational regulatory mechanism in PCa biology. These findings establish the CDK12-FOXA1-MDM2 axis as a pivotal driver of PCa progression and underscore the therapeutic potential of targeting FOXA1 phosphorylation to restore tumor suppressor function and induce apoptosis in PCa. Our work provides a mechanistic framework for developing precision therapies aimed at disrupting this oncogenic cascade in PCa.