PDF(Pubmed)
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.
摘要：
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。规避不可用N-Myc挑战的一种潜在方法是靶向维持N-Myc水平的蛋白质稳态(蛋白质稳态)系统。这里,我们确定热休克蛋白70（HSP70）是N-Myc的顶级伴侣，结合保守的“SELILKR”基序并阻止E3泛素连接酶的进入，STIP1同源性和含U盒蛋白1（STUB1），可能通过位阻。当HSP70在N-Myc上的停留时间通过用HSP70变构抑制剂处理而增加时，STUB1与N-Myc非常接近，并具有促进K416和K419位点上的N-Myc泛素化的功能，并形成由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NEPC肿瘤生长，增加了极光激酶A（AURKA）抑制剂的疗效，并限制神经内分泌相关通路的表达。
