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

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 wit...

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Autores principales: Yuan, Ye, Wang, Li‐Hong, Zhao, Xian‐Xian, Wang, Jiao, Zhang, Meng‐Si, Ma, Qing‐Hua, Wei, Sen, Yan, Ze‐Xuan, Cheng, Yue, Chen, Xiao‐Qing, Zou, Hong‐Bo, Ge, Jia, Wang, Yan, Zhang, Xia, Cui, You‐Hong, Luo, Tao, Bian, Xiu‐Wu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456703/
https://www.ncbi.nlm.nih.gov/pubmed/35848447
http://dx.doi.org/10.1002/cac2.12334
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author Yuan, Ye
Wang, Li‐Hong
Zhao, Xian‐Xian
Wang, Jiao
Zhang, Meng‐Si
Ma, Qing‐Hua
Wei, Sen
Yan, Ze‐Xuan
Cheng, Yue
Chen, Xiao‐Qing
Zou, Hong‐Bo
Ge, Jia
Wang, Yan
Zhang, Xia
Cui, You‐Hong
Luo, Tao
Bian, Xiu‐Wu
author_facet Yuan, Ye
Wang, Li‐Hong
Zhao, Xian‐Xian
Wang, Jiao
Zhang, Meng‐Si
Ma, Qing‐Hua
Wei, Sen
Yan, Ze‐Xuan
Cheng, Yue
Chen, Xiao‐Qing
Zou, Hong‐Bo
Ge, Jia
Wang, Yan
Zhang, Xia
Cui, You‐Hong
Luo, Tao
Bian, Xiu‐Wu
author_sort Yuan, Ye
collection PubMed
description 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 signaling pathways, inhibited the proliferation, invasion, and migration of GBM cells in vitro and in vivo. A rAAV dual‐vector system for packaging and delivery of dCas9‐VP64 was used to augment endogenous HUWE1 expression in vivo and showed an antitumor activity in glioma orthotopic xenografts. CONCLUSIONS: The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress GBM progression. Antitumor activity of rAAV dual‐vector delivering dCas9‐HUWE1 system uncovers a promising therapeutic strategy for GBM.
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spelling pubmed-94567032022-09-12 The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress glioblastoma progression Yuan, Ye Wang, Li‐Hong Zhao, Xian‐Xian Wang, Jiao Zhang, Meng‐Si Ma, Qing‐Hua Wei, Sen Yan, Ze‐Xuan Cheng, Yue Chen, Xiao‐Qing Zou, Hong‐Bo Ge, Jia Wang, Yan Zhang, Xia Cui, You‐Hong Luo, Tao Bian, Xiu‐Wu Cancer Commun (Lond) Original Articles 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 signaling pathways, inhibited the proliferation, invasion, and migration of GBM cells in vitro and in vivo. A rAAV dual‐vector system for packaging and delivery of dCas9‐VP64 was used to augment endogenous HUWE1 expression in vivo and showed an antitumor activity in glioma orthotopic xenografts. CONCLUSIONS: The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress GBM progression. Antitumor activity of rAAV dual‐vector delivering dCas9‐HUWE1 system uncovers a promising therapeutic strategy for GBM. John Wiley and Sons Inc. 2022-07-18 /pmc/articles/PMC9456703/ /pubmed/35848447 http://dx.doi.org/10.1002/cac2.12334 Text en © 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Yuan, Ye
Wang, Li‐Hong
Zhao, Xian‐Xian
Wang, Jiao
Zhang, Meng‐Si
Ma, Qing‐Hua
Wei, Sen
Yan, Ze‐Xuan
Cheng, Yue
Chen, Xiao‐Qing
Zou, Hong‐Bo
Ge, Jia
Wang, Yan
Zhang, Xia
Cui, You‐Hong
Luo, Tao
Bian, Xiu‐Wu
The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress glioblastoma progression
title The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress glioblastoma progression
title_full The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress glioblastoma progression
title_fullStr The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress glioblastoma progression
title_full_unstemmed The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress glioblastoma progression
title_short The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress glioblastoma progression
title_sort e3 ubiquitin ligase huwe1 acts through the n‐myc‐dll1‐notch1 signaling axis to suppress glioblastoma progression
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456703/
https://www.ncbi.nlm.nih.gov/pubmed/35848447
http://dx.doi.org/10.1002/cac2.12334
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