In this study, we uncover the critical role of p300/CBP-mediated histone H2B N terminus multisite lysine acetylation (H2BNTac) in defining oncogenic enhanceosomes in prostate cancer. Degradation of p300/CBP rapidly disables H2BNTac-marked oncogenic enhancers and represents a promising therapeutic strategy for enhancer-driven malignancies, including prostate cancer.