BAZ2A-mediated repression via H3K14ac-marked enhancers promotes prostate cancer stem cells

Prostate cancer (PCa) is one of the most prevalent cancers in men. Cancer stem cells are thought to be associated with PCa relapse. Here, we show that BAZ2A is required for PCa cells with a cancer stem-like state. BAZ2A genomic occupancy in PCa cells coincides with H3K14ac-enriched chromatin regions. This association is mediated by BAZ2A-bromodomain (BAZ2A-BRD) that specifically binds H3K14ac. BAZ2A associates with inactive enhancers marked by H3K14ac and repressing transcription of genes frequently silenced in aggressive and poorly differentiated PCa. BAZ2A-mediated repression is also linked to EP300 that acetylates H3K14ac. BAZ2A-BRD mutations or treatment with inhibitors abrogating BAZ2A-BRD/H3K14ac interaction impair PCa stem cells. Furthermore, pharmacological inactivation of BAZ2A-BRD impairs Pten-loss oncogenic transformation of prostate organoids. Our findings indicate a role of BAZ2A-BRD in PCa stem cell features and suggest potential epigenetic-reader therapeutic strategies to target BAZ2A in aggressive PCa.