CDK12 Inactivation Attenuates Prostate Cancer Progression by Inhibiting BNIP3-Mediated Mitophagy.

Abstract

Mitochondrial stress-induced mitophagy plays a critical role to maintain cellular homeostasis; however, in cancer cells, this process may also contribute to drug resistance. Our previous work identified CDK12 as a critical regulator of prostate cancer (PCa) cell survival under sustained enzalutamide exposure, though the precise mechanism remains to be elucidated. In this study, we hypothesize that CDK12 plays a key role in mitophagy regulation under mitochondrial stress, potentially modulating PCa cell resistance to enzalutamide, the first-line clinical medication in PCa therapy. Utilising multiple in vitro PCa cell models, we demonstrate that both CDK12 knockdown and pharmacological inhibition with THZ531 impaired mitophagy following treatment with enzalutamide and mitophagy inducer CCCP. Mechanistically, our finding reveal that CDK12 inhibition disrupts FOXO3-induced BNIP3 transcription, thereby preventing receptor-mediated mitophagy and sensitising PCa cells to enzalutamide. This study identifies the CDK12-FOXO3-BNIP3 pathway as a novel regulatory mechanism governing mitophagy under mitochondrial stress. Importantly, these results underscore CDK12's role in preserving mitochondrial function and promoting PCa cell survival during enzalutamide treatment. These findings highlight the therapeutic potential of targeting the CDK12-BNIP3-mitophagy axis in combination with antiandrogen therapies, offering a promising strategy to overcome drug resistance in PCa and improve clinical outcomes.