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Proteostasis perturbation of N-Myc leveraging HSP70 mediated protein turnover improves treatment of neuroendocrine prostate cancer

Author

Listed:
  • Pengfei Xu

    (University of California)

  • Joy C. Yang

    (University of California)

  • Bo Chen

    (University of California
    Sichuan University)

  • Shu Ning

    (University of California)

  • Xiong Zhang

    (University of California)

  • Leyi Wang

    (University of California
    University of California)

  • Christopher Nip

    (University of California)

  • Yuqiu Shen

    (University of California)

  • Oleta T. Johnson

    (University of California)

  • Gabriela Grigorean

    (University of California)

  • Brett Phinney

    (University of California)

  • Liangren Liu

    (Sichuan University)

  • Qiang Wei

    (Sichuan University)

  • Eva Corey

    (University of Washington)

  • Clifford G. Tepper

    (University of California
    Davis Comprehensive Cancer Center)

  • Hong-Wu Chen

    (University of California
    Davis Comprehensive Cancer Center)

  • Christopher P. Evans

    (University of California
    Davis Comprehensive Cancer Center)

  • Marc A. Dall’Era

    (University of California
    Davis Comprehensive Cancer Center)

  • Allen C. Gao

    (University of California
    Davis Comprehensive Cancer Center)

  • Jason E. Gestwicki

    (University of California)

  • Chengfei Liu

    (University of California
    University of California
    Davis Comprehensive Cancer Center)

Abstract

N-Myc is a key driver of neuroblastoma and neuroendocrine prostate cancer (NEPC). One potential way to circumvent the challenge of undruggable N-Myc is to target the protein homeostasis (proteostasis) system that maintains N-Myc levels. Here, we identify heat shock protein 70 (HSP70) as a top partner of N-Myc, which binds a conserved “SELILKR” motif and prevents the access of E3 ubiquitin ligase, STIP1 homology and U-box containing protein 1 (STUB1), possibly through steric hindrance. When HSP70’s dwell time on N-Myc is increased by treatment with the HSP70 allosteric inhibitor, STUB1 is in close proximity with N-Myc and becomes functional to promote N-Myc ubiquitination on the K416 and K419 sites and forms polyubiquitination chains linked by the K11 and K63 sites. Notably, HSP70 inhibition significantly suppressed NEPC tumor growth, increased the efficacy of aurora kinase A (AURKA) inhibitors, and limited the expression of neuroendocrine-related pathways.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50459-x
    DOI: 10.1038/s41467-024-50459-x
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    References listed on IDEAS

    as
    1. 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.
    2. F. Ulrich Hartl & Andreas Bracher & Manajit Hayer-Hartl, 2011. "Molecular chaperones in protein folding and proteostasis," Nature, Nature, vol. 475(7356), pages 324-332, July.
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