Postdoctoral Scholars Association

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer characterized by N-Myc (MYCN) amplification. Due to N-Myc’s disordered domains and lack of druggable sites, targeting its proteostasis offers a novel therapeutic angle. Here, we investigated the molecular chaperones involved in regulating N-Myc protein turnover. Mass spectrometry analysis following N-Myc pulldown identified several HSP70 family proteins as prominent interactors. Functional assays revealed that HSP70 interacts with N-Myc and recruits the E3 ligase STUB1 to facilitate ubiquitination at lysines 416 and 419, targeting N-Myc for K11-linked polyubiquitin-mediated proteasomal degradation. This interaction was dependent on a conserved degron motif, SELILKR, within the N-Myc protein. siRNA-mediated knockdown of N-Myc significantly reduced cell proliferation in NEPC models, underscoring its oncogenic importance. Our findings reveal a novel HSP70-STUB1-N-Myc regulatory axis and suggest a potential vulnerability in NEPC that could be exploited therapeutically through proteostasis-targeting strategies.