ARID1A, encoding a subunit of the SWI/SNF chromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with this genetic characteristic remain to be explored. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small-molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated tumours. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumours. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylates Lys120 of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates the apoptosis-promoting function of p53 by upregulating HDAC6. Together, these results indicate that pharmacological inhibition of HDAC6 is a therapeutic strategy for ARID1A-mutated cancers.

中文翻译：

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ARID1A 突变的卵巢癌依赖于 HDAC6 活性。

ARID1A 编码 SWI/SNF 染色质重塑复合体的一个亚基，是所有人类癌症中最常发生突变的表观遗传调节因子。ARID1A 和 TP53 突变通常是相互排斥的。与这种遗传特征相关的治疗方法仍有待探索。在这里，我们表明 HDAC6 活性在 ARID1A 突变的卵巢癌中是必不可少的。使用临床适用的小分子抑制剂抑制 HDAC6 活性显着提高了携带 ARID1A 突变肿瘤的小鼠的存活率。这与抑制 ARID1A 突变的肿瘤的生长和传播有关，但与野生型肿瘤无关。ARID1A 突变细胞中对 HDAC6 活性的依赖与 ARID1A 对 HDAC6 的直接转录抑制相关。HDAC6 抑制选择性促进 ARID1A 突变细胞的凋亡。HDAC6 直接使 p53 的 Lys120 去乙酰化，这是一种促凋亡的翻译后修饰。因此，ARID1A 突变通过上调 HDAC6 使 p53 的凋亡促进功能失活。总之，这些结果表明 HDAC6 的药理学抑制是 ARID1A 突变癌症的治疗策略。