ASC-J9 suppresses renal cell carcinoma progression by targeting an androgen receptor-dependent HIF2α/VEGF signaling pathway

Males have a higher incidence of renal cell carcinoma (RCC) than females, but the reason for this gender difference is unknown. Addressing this question, we report the discovery of an androgen receptor (AR)-induced HIF2α/VEGF signal that drives RCC progression. AR attenuation or augmentation in RCC cells altered their proliferation, migration, and invasion in multiple models in vitro and in vivo. Mechanistic investigations revealed that AR targeting inhibited RCC cell migration and invasion by modulating HIF2α/VEGF signals at the level of mRNA and protein expression. Interrupting HIF2α/VEGF signals with inhibitors of either HIF2α or VEGF was sufficient to suppress RCC progression. Similarly, the specific AR degradation enhancer ASC-J9 was sufficient to suppress AR-induced HIF2α/VEGF signaling and RCC progression in multiple models in vitro and in vivo. Taken together, our results revealed a novel role for AR in RCC initiation and progression with implications for novel therapeutic strategies.