p300-mediated acetylation of KCNN4 drives enzalutamide resistance in prostate cancer.

Enzalutamide resistance remains a critical obstacle in the treatment of castration-resistant prostate cancer (CRPC), with potassium calcium-activated channel subfamily N member 4 (KCNN4) emerging as a key mediator of therapeutic failure. Here, we demonstrate that KCNN4 is significantly upregulated in enzalutamide-resistant PCa cells and clinical tissues, correlating with poor prognosis. Mechanistically, p300, a histone acetyltransferase, directly binds to KCNN4 and mediates its acetylation at lysine 16, which competitively inhibits ubiquitination-mediated degradation, thereby stabilizing KCNN4 protein. Notably, p300 inhibition disrupts KCNN4 acetylation, restores its proteasomal degradation, and resensitizes resistant cells to enzalutamide both in vitro and in vivo. Moreover, KCNN4 knockdown suppresses tumor growth and synergizes with enzalutamide in xenograft models, underscoring the therapeutic potential of targeting the p300-KCNN4 axis. Collectively, our findings reveal a previously unrecognized epigenetic regulatory mechanism coupling p300-mediated acetylation to potassium channel stability, providing a promising therapeutic strategy to overcome chemoresistance in advanced prostate cancer.