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.

中文翻译：

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BAZ2A 介导的 H3K14ac 标记增强子抑制促进前列腺癌干细胞

前列腺癌 (PCa) 是男性最常见的癌症之一。癌症干细胞被认为与 PCa 复发有关。在这里，我们表明 BAZ2A 是癌症干细胞样状态的 PCa 细胞所必需的。PCa 细胞中的 BAZ2A 基因组占据与富含 H3K14ac 的染色质区域一致。这种关联是由特异性结合 H3K14ac 的 BAZ2A-溴结构域 (BAZ2A-BRD) 介导的。BAZ2A 与 H3K14ac 标记的非活性增强子相关，并抑制在侵袭性和低分化 PCa 中经常沉默的基因转录。BAZ2A 介导的抑制也与乙酰化 H3K14ac 的 EP300 相关。BAZ2A-BRD 突变或用消除 BAZ2A-BRD/H3K14ac 相互作用的抑制剂治疗会损害 PCa 干细胞。此外，BAZ2A-BRD 的药理学失活会损害Pten-前列腺类器官的致癌转化损失。我们的研究结果表明 BAZ2A-BRD 在 PCa 干细胞特征中的作用，并提出了潜在的表观遗传阅读器治疗策略，以靶向 BAZ2A 在侵袭性 PCa 中。