Histone deacetylase (HDAC) proteins are epigenetic regulators that govern a wide variety of cellular events. With a role in cancer formation, HDAC inhibitors have emerged as anti-cancer therapeutics. Among the eleven metal-dependent class I, II, and IV HDAC proteins targeted by inhibitor drugs, class IIa HDAC4, -5, -7, and -9 harbor low deacetylase activity and are hypothesized to be “reader” proteins, which bind to post-translationally acetylated lysine. However, evidence linking acetyllysine binding to a downstream functional event is lacking. Here, we report for the first time that HDAC4, -5, and -7 dissociated from corepressor NCoR in the presence of an acetyllysine-containing peptide, consistent with reader function. Documenting the biological consequences of this possible reader function, mutation of a critical acetylation site regulated androgen receptor (AR) transcriptional activation function through HDAC7-NCoR-HDAC3 dissociation. The data document the first evidence consistent with epigenetic-reader functions of class IIa HDAC proteins.

组蛋白脱乙酰酶 (HDAC) 蛋白是控制多种细胞事件的表观遗传调节因子。HDAC 抑制剂在癌症形成中发挥作用，已成为抗癌疗法。在抑制剂药物靶向的 11 种金属依赖性 I、II 和 IV 类 HDAC 蛋白中，IIa 类 HDAC4、-5、-7 和 -9 具有低脱乙酰酶活性，被假设为“读取器”蛋白，它们与翻译后乙酰化赖氨酸。然而，缺乏将乙酰赖氨酸结合与下游功能事件联系起来的证据。在这里，我们首次报告 HDAC4、-5 和 -7 在含有乙酰赖氨酸的肽存在下从辅阻遏物 NCoR 解离，这与阅读器功能一致。记录这种可能的阅读器功能的生物学后果，关键乙酰化位点的突变通过 HDAC7-NCoR-HDAC3 解离调节雄激素受体 (AR) 转录激活功能。这些数据记录了与 IIa 类 HDAC 蛋白的表观遗传阅读器功能一致的第一个证据。