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突变的卵巢癌取决于HDAC6活性

编码SWI / SNF染色质重塑复合体的亚基的ARID1A是所有人类癌症中最常见的突变表观遗传调控因子。ARID1A和TP53突变通常是互斥的。与这种遗传特征相关的治疗方法仍有待探索。在这里，我们显示HDAC6活性在ARID1A突变的卵巢癌中至关重要。使用临床上可用的小分子抑制剂抑制HDAC6活性可显着提高携带ARID1A突变肿瘤的小鼠的存活率。这与抑制ARID1A突变（而非野生型）肿瘤的生长和扩散有关。对HDAC6活性的依赖性ARID1A突变的细胞与ARID1A对HDAC6的直接转录抑制有关。HDAC6抑制选择性促进ARID1A突变细胞的凋亡。HDAC6直接使p53的Lys120脱乙酰，这是一种促凋亡的翻译后修饰。因此，ARID1A突变通过上调HDAC6激活p53的凋亡促进功能。总之，这些结果表明，HDAC6的药理学抑制作用是针对ARID1A突变的癌症的治疗策略。