The E2F3 transcriptional regulatory pathway plays a major part in multiple-cancer progression, but the specific contributions of this pathway to tumor formation and the progression of clear cell renal cell carcinoma (ccRCC) are not fully understood. Clinically, we demonstrated that E2F3 was overexpressed in advanced tumor features. Moreover, cytoplasmic restoration predicted the poor overall survival of ccRCC patients. As a remarkable oncogene for ccRCC, high HIF-2α levels closely correlated with E2F3 upregulation. We observed in vitro that E2F3 overexpression and knockdown regulated HIF-2α expression. Furthermore, we found that HIF-2α harbored multiple E2F3 binding sites in the promoters. Mechanistically, E2F3 acted to transactivate HIF-2α transcription, which in turn exerted a serial effect on the pivotal epithelial-mesenchymal transition-related genes. The RNA interference-mediated silencing of HIF-2α attenuated E2F3-enhanced cell migration and invasion in vitro and in vivo. Overall, our results identified HIF-2α as a direct target gene for E2F3 upregulation, which was critical for carcinogenesis and progression of ccRCC. Thus, targeting the E2F3-HIF-2α interaction may be a promising approach to ccRCC treatment.
Oncotarget. 2016 Jul 13 [Epub ahead of print]
Yu Gao, Hongzhao Li, Xin Ma, Yang Fan, Dong Ni, Yu Zhang, Qingbo Huang, Kan Liu, Xintao Li, Lei Wang, Yuanxin Yao, Qing Ai, Xu Zhang
Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China., Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China., Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China., Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China., Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China., Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China., Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China., Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China., Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China., Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China., Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China., Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China., Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China.