Inactivation of BRM/SMARCA2 sensitizes clear cell renal cell carcinoma to histone deacetylase complex inhibitors.

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.