E2F3 upregulation promotes tumor malignancy through the transcriptional activation of HIF-2α in clear cell renal cell carcinoma

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-2 alpha levels closely correlated with E2F3 upregulation. We observed in vitro that E2F3 overexpression and knockdown regulated HIF-2 alpha expression. Furthermore, we found that HIF-2 alpha harbored multiple E2F3 binding sites in the promoters. Mechanistically, E2F3 acted to transactivate HIF-2 alpha transcription, which in turn exerted a serial effect on the pivotal epithelial-mesenchymal transition-related genes. The RNA interference-mediated silencing of HIF-2 alpha attenuated E2F3-enhanced cell migration and invasion in vitro and in vivo. Overall, our results identified HIF-2 alpha as a direct target gene for E2F3 upregulation, which was critical for carcinogenesis and progression of ccRCC. Thus, targeting the E2F3-HIF-2 alpha interaction may be a promising approach to ccRCC treatment.