Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer (Affymetrix)

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. Gene expression profiling of drug-resistant LNCaP-C42B castration-resistant prostate cancer (CRPC) cells was performed in order to define genes exhibiting altered expression relative to the untreated, LNCaP-C42B parental cell line. For this, drug-resistant cells were generated and maintained by long-term culture in enzalutamide (MDV3100) or abiraterone. Total cellular RNA was isolated and then microarray gene expression profiling performed with Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays.