Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, China.
Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, China.
Pathol Res Pract. 2020 Apr;216(4):152867. doi: 10.1016/j.prp.2020.152867. Epub 2020 Feb 11.
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.
BRM 是 SWI/SNF 染色质重塑复合物的关键亚基，是多种肿瘤中的重要肿瘤抑制基因。BRM 没有突变，而是在多种肿瘤类型中被表观遗传沉默，这与许多抗癌基因不同。此外，组蛋白去乙酰化酶复合物（HDAC）抑制剂已知可逆转 BRM 沉默，但它们也通过乙酰化其 C 末端使其失活。已经报道 HDAC 抑制剂在药理学上恢复 BRM 并抑制癌细胞生长方面是有效的。但是，我们不知道哪种 HDAC 抑制剂（如果有的话）可以在透明细胞肾细胞癌（RCC）中明确调节 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 蛋白表达。尽管这些 HDAC 抑制剂能够恢复 BRM 表达，但在存在时也会阻止 BRM 功能。然而，在它们被去除后，我们观察到 BRM 表达在几天内仍然升高，并且在此期间检测到 BRM 活性。此外，HDAC3 和 HDAC9 调节 BRM 的表达和功能，特别是对于 HDAC3 抑制剂 RGFP966。我们的研究表明，BRM 的敲低促进了 RCC 细胞的增殖、迁移和侵袭。RGFP966 通过在体内和体外恢复 BRM 表达来抑制透明细胞 RCC 的肿瘤进展。总之，HDAC3 是临床治疗的潜在靶点，我们的研究为 BRM 阴性透明细胞 RCC 的靶向治疗提供了一种新方法。
