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

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.
Mesh Terms:
Androstenes, Angiogenesis Inhibitors, Animals, Cell Line, Tumor, HSP70 Heat-Shock Proteins, Humans, Male, Mice, Molecular Docking Simulation, Neoplasm Grading, Phenylthiohydantoin, Prostate, Prostatic Neoplasms, Prostatic Neoplasms, Castration-Resistant, Proteasome Endopeptidase Complex, Proteostasis, Receptors, Androgen, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination
Nat Commun
Date: Dec. 16, 2017
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