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

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, Clifford G. Tepper, Hong-Wu Chen, Christopher P. Evans, Marc A. Dall’Era, Allen C. Gao, Jason E. Gestwicki and Chengfei Liu ()
Additional contact information
Pengfei Xu: University of California
Joy C. Yang: University of California
Bo Chen: University of California
Shu Ning: University of California
Xiong Zhang: University of California
Leyi Wang: 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
Hong-Wu Chen: University of California
Christopher P. Evans: University of California
Marc A. Dall’Era: University of California
Allen C. Gao: University of California
Jason E. Gestwicki: University of California
Chengfei Liu: University of California

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50459-x

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