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.
Nature communications. 2024 Aug 05*** epublish ***
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, Chengfei Liu
Department of Urologic Surgery, University of California, Davis, CA, USA., Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA., Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA., Proteomics Core Facility, University of California, Davis, CA, USA., Department of Urology, West China Hospital, Sichuan University, Sichuan, China., Department of Urology, University of Washington, Washington, WA, USA., Department of Urologic Surgery, University of California, Davis, CA, USA. .