POLR2A Drives Tumor Cell Aggressive in Both VHL and PBRM1 Mutation Renal-Cell Carcinoma

Background: Loss of VHL always results in the loss of PBRM1 and causes aggressive clear cell renal cell carcinoma. However, VHL mutation was not significantly associated with worse survival, and PBRM1 modulate the tumor behavior is not clear. Thus, exploration of key molecules promoting the tumor aggressive is urgent in both VHL and PBRM1 RCC patient.Methods and results: POLR2A was screened out by analyzing The Cancer Genome Atlas mutation data. Gene Set Enrichment Analysis results showed that E2F, G2M, and mTOR1 pathways were all altered in response to POLR2A high expression. Furthermore, In vitro, knockdown of POLR2A in 769-P and 786-O cells resulted in cell growth arrest and cell cycle blockade compared to control cells, the mechanism though decreasing cyclin D1-CDK4 axis. In vivo results were confirmed 786-O cells in which POLR2A expression was silenced, exhibited tumor growth inhibited compared to control group.Conclusions: POLR2A was the key protein after VHL and PBRM1 mutations in RCC, inhibition of POLR2A crippled cell viability and proliferation in vivo and in vitro, We anticipate POLR2A represents a novel candidate for RCC treatment.