Department of Urologic Surgery, University of California, Davis, CA, USA.
Department of Urology, West China Hospital, Sichuan University, Sichuan, China.
Nat Commun. 2024 Aug 5;15(1):6626. doi: 10.1038/s41467-024-50459-x.
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.
N-Myc 是神经母细胞瘤和神经内分泌前列腺癌（NEPC）的关键驱动因素。规避难以靶向的 N-Myc 这一挑战的一种潜在方法是针对维持 N-Myc 水平的蛋白质稳态（proteostasis）系统。在这里，我们确定热休克蛋白 70（HSP70）为 N-Myc 的顶级伴侣，它与保守的“SELILKR”基序结合，并通过空间位阻防止 E3 泛素连接酶、STIP1 同源和 U -box 含有蛋白 1（STUB1）的接近，可能通过空间位阻来防止接近。当 HSP70 的别构抑制剂增加 HSP70 在 N-Myc 上的停留时间时，STUB1 与 N-Myc 紧密接近并变得能够促进 N-Myc 在 K416 和 K419 位点上的泛素化，并形成通过 K11 和 K63 位点连接的多泛素化链。值得注意的是，HSP70 抑制显著抑制了 NEPC 肿瘤的生长，提高了极光激酶 A（AURKA）抑制剂的疗效，并限制了神经内分泌相关途径的表达。
