2. Academic Validation
  3. Proteostasis perturbation of N-Myc leveraging HSP70 mediated protein turnover improves treatment of neuroendocrine prostate cancer

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

  • Nat Commun. 2024 Aug 5;15(1):6626. doi: 10.1038/s41467-024-50459-x.
Pengfei Xu # 1,  Joy C Yang # 1,  Bo Chen # 1 2,  Shu Ning 1,  Xiong Zhang 3,  Leyi Wang 1 4,  Christopher Nip 1,  Yuqiu Shen 1,  Oleta T Johnson 5,  Gabriela Grigorean 6,  Brett Phinney 6,  Liangren Liu 2,  Qiang Wei 2,  Eva Corey 7,  Clifford G Tepper 3 8,  Hong-Wu Chen 3 8,  Christopher P Evans 1 8,  Marc A Dall'Era 1 8,  Allen C Gao 1 8,  Jason E Gestwicki 5,  Chengfei Liu 9 10 11
Affiliations

Affiliations

  • 1 Department of Urologic Surgery, University of California, Davis, CA, USA.
  • 2 Department of Urology, West China Hospital, Sichuan University, Sichuan, China.
  • 3 Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA.
  • 4 Graduate Group in Integrative Pathobiology, University of California, Davis, CA, USA.
  • 5 Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
  • 6 Proteomics Core Facility, University of California, Davis, CA, USA.
  • 7 Department of Urology, University of Washington, Washington, WA, USA.
  • 8 University of California, Davis Comprehensive Cancer Center, Sacramento, CA, USA.
  • 9 Department of Urologic Surgery, University of California, Davis, CA, USA. cffliu@ucdavis.edu.
  • 10 Graduate Group in Integrative Pathobiology, University of California, Davis, CA, USA. cffliu@ucdavis.edu.
  • 11 University of California, Davis Comprehensive Cancer Center, Sacramento, CA, USA. cffliu@ucdavis.edu.
  • # Contributed equally.
PMID: 39103353 DOI: 10.1038/s41467-024-50459-x
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.

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