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

Author

Listed:
  • Chengfei Liu

    (University of California Davis)

  • Wei Lou

    (University of California Davis)

  • Joy C. Yang

    (University of California Davis)

  • Liangren Liu

    (Sichuan University)

  • Cameron M. Armstrong

    (University of California Davis)

  • Alan P. Lombard

    (University of California Davis)

  • Ruining Zhao

    (General Hospital of Ningxia Medical University)

  • Onika D. V. Noel

    (University of California Davis)

  • Clifford G. Tepper

    (University of California Davis
    University of California Davis)

  • Hong-Wu Chen

    (University of California Davis
    University of California Davis
    VA Northern California Health Care System)

  • Marc Dall’Era

    (University of California Davis
    University of California Davis)

  • Christopher P. Evans

    (University of California Davis
    University of California Davis)

  • Allen C. Gao

    (University of California Davis
    University of California Davis
    VA Northern California Health Care System)

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.

Suggested Citation

  • Chengfei Liu & Wei Lou & Joy C. Yang & Liangren Liu & Cameron M. Armstrong & Alan P. Lombard & Ruining Zhao & Onika D. V. Noel & Clifford G. Tepper & Hong-Wu Chen & Marc Dall’Era & Christopher P. Evan, 2018. "Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07178-x
    DOI: 10.1038/s41467-018-07178-x
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    Cited by:

    1. Pengfei Xu & Joy C. Yang & Bo Chen & Shu Ning & Xiong Zhang & Leyi Wang & Christopher Nip & Yuqiu Shen & Oleta T. Johnson & Gabriela Grigorean & Brett Phinney & Liangren Liu & Qiang Wei & Eva Corey & , 2024. "Proteostasis perturbation of N-Myc leveraging HSP70 mediated protein turnover improves treatment of neuroendocrine prostate cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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