GSE120004
Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer (RNA-Seq)
Constitutively active androgen receptor (AR) signaling confers resistance to AR-targeted therapies. Here we show that the ubiquitin-mediated proteolysis pathway plays a critical role in the degradation of AR and its variants, particularly variant 7 (AR-V7). AR/AR-V7 proteinhomeostasis (proteostasis) requires interaction of the E3 ubiquitin ligase STUB1 and HSP70complex. STUB1 disassociates AR/AR-V7 from HSP70, leading to AR/AR-V7 ubiquitination and degradation. Inhibition of HSP70 reduces AR/AR-V7 expression which significantly inhibits prostate tumor growth and improves enzalutamide/abiraterone treatments. Clinically, HSP70 expression is upregulated and correlated with AR/AR-V7 levels in high Gleason scores prostate tumors. Our results reveal a novel mechanism of AR-V7 modulation via proteostasis which could be targeted to reduce AR-V7 expression and overcome resistance to AR-targeted therapies. Overall design: A total of 6 samples were analyzed in this study. The study included 2 different castration-resisatnt prostate cancer (CRPC) cell lines, LNCaP-C42B-MDVR and CWR22Rv1. Individual cultures of each cell line were treated with DMSO vehicle control, apoptozole, or VER155008. Following treatment of the cells for 48 hours, total RNA was isolated and then submitted for RNA-sequencing analysis.