ARID1A-mutated ovarian cancers depend on HDAC6 activity.
ARID1A-mutated ovarian cancers depend on HDAC6 activity.
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DOI：
10.1038/ncb3582
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发表时间：
2017-08
影响因子：
21.3
通讯作者：
Zhang R
中科院分区：
文献类型：
--
作者：
Bitler BG;Wu S;Park PH;Hai Y;Aird KM;Wang Y;Zhai Y;Kossenkov AV;Vara-Ailor A;Rauscher FJ III;Zou W;Speicher DW;Huntsman DG;Conejo-Garcia JR;Cho KR;Christianson DW;Zhang R
ARID 1A编码SWI/SNF染色质重塑复合物的亚基，是所有人类癌症中最常突变的表观遗传调节因子。ARID 1A和TP 53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，我们表明HDAC 6活性在ARID 1A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HDAC 6活性显著改善了携带ARID 1A突变肿瘤的小鼠的存活率。这与抑制ARID 1A突变型肿瘤的生长和传播有关，但与野生型肿瘤无关。ARID 1A突变细胞中对HDAC 6活性的依赖性与ARID 1A对HDAC 6的直接转录抑制相关。HDAC 6抑制选择性地促进ARID 1A突变细胞的凋亡。HDAC 6直接使p53的Lys-120脱乙酰基，这是一种促凋亡的翻译后修饰。因此，ARID 1A突变通过上调HDAC 6使p53的促凋亡功能失活。总之，这些结果表明HDAC 6的药理学抑制是ARID 1A突变癌症的治疗策略。
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 wildtype, 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 Lys-120 of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates p53’s apoptosis-promoting function by upregulating HDAC6. Together, these results indicate that pharmacological inhibition of HDAC6 is a therapeutic strategy for ARID1A-mutated cancers.
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影响因子：
64.5
作者：
Kawaguchi, Y;Kovacs, JJ;Yao, TP
通讯作者：
Yao, TP
哺乳动物SWI/SNF复合物的蛋白质组学和生物信息学分析确定了在人类恶性肿瘤中的广泛作用。
影响因子：
30.8
作者：
Kadoch, Cigall;Hargreaves, Diana C.;Hodges, Courtney;Elias, Laura;Ho, Lena;Ranish, Jeff;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
10.3
作者：
Guan, Bin;Rahmanto, Yohan Suryo;Shih, Ie-Ming
通讯作者：
Shih, Ie-Ming
影响因子：
14.8
作者：
Hai Y;Christianson DW
通讯作者：
Christianson DW