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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE120006 | GEO | 2018/10/05

REPOSITORIES: GEO

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

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Project description: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.

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