Inactivation of BRM/SMARCA2 sensitizes clear cell renal cell carcinoma to histone deacetylase complex inhibitors
Inactivation of BRM/SMARCA2 sensitizes clear cell renal cell carcinoma to histone deacetylase complex inhibitors
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BRM/SMARCA2 失活使透明细胞肾细胞癌对组蛋白脱乙酰酶复合物抑制剂敏感
DOI：
10.1016/j.prp.2020.152867
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发表时间：
2020-04-01
影响因子：
2.8
通讯作者：
Rao, Qiu
中科院分区：
文献类型：
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作者：
Fang, Ru;Pan, Rui;Rao, Qiu
BRM是SWI/SNF染色质重塑复合体的关键亚单位，是多种肿瘤中重要的抑癌基因。BRM不是突变，而是在多种肿瘤类型中表观遗传沉默，这与许多抗癌基因不同。此外，组蛋白脱乙酰酶复合体(HDAC)抑制剂已知可以逆转BRM沉默，但它们也通过其C末端的乙酰化来使其失活。据报道，HDAC抑制剂在药物修复BRM方面有效，从而抑制癌细胞生长。但我们不知道哪种HDAC抑制剂(如果有的话)能调节肾透明细胞癌(RCC)的BRM。通过使用七种类型的HDAC抑制剂，我们发现泛HDAC抑制剂恢复了BRM蛋白的表达。尽管它们有能力恢复BRM的表达，但这些HDAC抑制剂在存在时也会阻断BRM的功能。然而，在去除它们之后，我们观察到BRM的表达在几天内保持高水平，并在此期间检测到BRM的活性。此外，HDAC3和HDAC9还调节BRM的表达和功能，尤其是对HDAC3抑制剂RGFP966。我们的研究表明，BRM基因的敲除促进了肾癌细胞的增殖、迁移和侵袭。RGFP966在体内和体外均通过恢复BRM的表达来抑制透明细胞肾癌的肿瘤进展。综上所述，HDAC3是临床治疗的潜在靶点，我们的研究为BRM阴性的透明细胞肾癌的靶向治疗提供了新的途径。
BRM, a key subunit of the SWI/SNF chromatin remodeling complex, is an important tumor suppressor gene in multiple tumors. BRM is not mutated, but rather epigenetically silenced in a variety of tumor types, which is different from many anti-cancer genes. In addition, histone deacetylase complex (HDAC) inhibitors are known to reverse BRM silencing, but they also inactivate it via acetylation of its c-terminus. HDAC inhibitors have been reported to be effective at pharmacologically restoring BRM and thereby inhibiting cancer cell growth. But we do not know which HDAC inhibitor, if any, regulate BRM in clear cell renal cell carcinoma (RCC). By using seven types of HDAC inhibitors, we found that Pan-HDAC inhibitors restored BRM protein expression. Despite their ability to restore BRM expression, these HDAC inhibitors also blocked BRM function when present. However, after their removal, we observed that BRM expression remained elevated for several days, and during this period, BRM activity was detected. In addition, HDAC3 and HDAC9 regulate BRM expression and function, especially for HDAC3 inhibitor, RGFP966. Our study demonstrated that knockdown of BRM promoted RCC cells proliferation, migration and invasion. RGFP966 inhibited the tumor progression of clear cell RCC by restoring BRM expression both in vivo and in vitro. In conclusion, HDAC3 is potential targets for clinical treatment, and our study provides a new approach for targeted therapy of BRM-negative clear cell RCC.