The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress glioblastoma progression

作者：Ye Yuan, Lihong Wang, Xianxian Zhao, Jiao Wang, Mengsi Zhang, Qinghua Ma, Sen Wei, Zexuan Yan, Yue Cheng, Xiao‐Qing Chen, Hongbo Zou, Jia Ge, Yan Wang, Xia Zhang, You‐Hong Cui, Tao Luo, Xiu‐Wu Bian · 发表于：癌症：英文版 · 年份：2022 · DOI：10.1002/cac2.12334 · 被引用次数：25 · 研究领域：Ubiquitin and proteasome pathways、Protein Degradation and Inhibitors、Microtubule and mitosis dynamics

BACKGROUND: Elucidation of the post-transcriptional modification has led to novel strategies to treat intractable tumors, especially glioblastoma (GBM). The ubiquitin-proteasome system (UPS) mediates a reversible, stringent and stepwise post-translational modification which is closely associated with malignant processes of GBM. To this end, developing novel therapeutic approaches to target the UPS may contribute to the treatment of this disease. This study aimed to screen the vital and aberrantly regulated component of the UPS in GBM. Based on the molecular identification, functional characterization, and mechanism investigation, we sought to elaborate a novel therapeutic strategy to target this vital factor to combat GBM. METHODS: We combined glioma datasets and human patient samples to screen and identify aberrantly regulated E3 ubiquitin ligase. Multidimensional database analysis and molecular and functional experiments in vivo and in vitro were used to evaluate the roles of HECT, UBA and WWE domain-containing E3 ubiquitin ligase 1 (HUWE1) in GBM. dCas9 synergistic activation mediator system and recombinant adeno-associated virus (rAAV) were used to endogenously overexpress full-length HUWE1 in vitro and in glioma orthotopic xenografts. RESULTS: Low expression of HUWE1 was closely associated with worse prognosis of GBM patients. The ubiquitination and subsequent degradation of N-Myc mediated by HUWE1, leading to the inactivation of downstream Delta-like 1 (DLL1)-NOTCH1 sig...