Proteostasis perturbation of N-Myc leveraging HSP70 mediated protein turnover improves treatment of neuroendocrine prostate cancer
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.
Authors
- Clifford G. Tepper (ORCID: https://orcid.org/0000-0001-7105-1102)
- Eva Corey (ORCID: https://orcid.org/0000-0002-9244-3807)
- Oleta T. Johnson (ORCID: https://orcid.org/0000-0001-5170-3003)
- Gabriela Grigorean (ORCID: https://orcid.org/0000-0001-5693-0846)
- Allen C. Gao (ORCID: https://orcid.org/0000-0002-5966-9038)
- Qiang Wei (ORCID: https://orcid.org/0000-0001-9926-1646)
- Christopher Nip
- Jason E. Gestwicki (ORCID: https://orcid.org/0000-0002-6125-3154)
- Pengfei Xu (ORCID: https://orcid.org/0000-0002-9401-9487)
- Shu Ning (ORCID: https://orcid.org/0000-0002-6514-0376)
- Marc Dall’Era (ORCID: https://orcid.org/0000-0002-2301-2683)
- Brett S. Phinney (ORCID: https://orcid.org/0000-0003-3870-3302)
- Joy C. Yang (ORCID: https://orcid.org/0000-0001-9162-481X)
- Christopher P. Evans (ORCID: https://orcid.org/0000-0001-5626-8901)
- Bo Chen (ORCID: https://orcid.org/0000-0003-2768-9007)
- Xiong Zhang (ORCID: https://orcid.org/0000-0002-9214-396X)
- Yuqiu Shen
- Chengfei Liu (ORCID: https://orcid.org/0000-0002-2452-8788)
- Leyi Wang (ORCID: https://orcid.org/0009-0008-7297-0643)
- Liangren Liu (ORCID: https://orcid.org/0000-0001-7597-6241)
- Hong-Wu Chen
Institutions
- University of California, San Francisco (US)
- University of Washington (US)
- Sichuan University (CN)
- University of California System (US)
- West China Hospital of Sichuan University (CN)
- Integra (United States) (US)
- UC Davis Comprehensive Cancer Center
- University of California, Davis (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-05
- DOI
- https://doi.org/10.1038/s41467-024-50459-x
- Citations
- 6
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- U.S. Department of Defense
- National Institutes of Health
- University of California, Davis
- National Cancer Institute
- Comprehensive Cancer Center, University of California, Davis
- Congressionally Directed Medical Research Programs