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

Abstract：

:Protein homeostasis (proteostasis) is a potential mechanism that contributes to cancer cell survival and drug resistance. Constitutively active androgen receptor (AR) variants confer anti-androgen resistance in advanced prostate cancer. However, the role of proteostasis involved in next generation anti-androgen resistance and the mechanisms of AR variant regulation are poorly defined. Here we show that the ubiquitin-proteasome-system (UPS) is suppressed in enzalutamide/abiraterone resistant prostate cancer. AR/AR-V7 proteostasis requires the interaction of E3 ubiquitin ligase STUB1 and HSP70 complex. STUB1 disassociates AR/AR-V7 from HSP70, leading to AR/AR-V7 ubiquitination and degradation. Inhibition of HSP70 significantly inhibits prostate tumor growth and improves enzalutamide/abiraterone treatments through AR/AR-V7 suppression. Clinically, HSP70 expression is upregulated and correlated with AR/AR-V7 levels in high Gleason score prostate tumors. Our results reveal a novel mechanism of anti-androgen resistance via UPS alteration which could be targeted through inhibition of HSP70 to reduce AR-V7 expression and overcome resistance to AR-targeted therapies.

journal_name

Nat Commun

journal_title

Nature communications

authors

Liu C,Lou W,Yang JC,Liu L,Armstrong CM,Lombard AP,Zhao R,Noel ODV,Tepper CG,Chen HW,Dall'Era M,Evans CP,Gao AC

doi

10.1038/s41467-018-07178-x

subject

Has Abstract

pub_date

2018-11-16 00:00:00

pages

4700

issue

1

issn

2041-1723

pii

10.1038/s41467-018-07178-x

journal_volume

9

pub_type

杂志文章

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