Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitination

Xiaoguang Fang; Wenchao Zhou; Qiulian Wu; Zhi Huang; Yu Shi; Kailin Yang; Cong Chen; Qi Xie; Stephen C Mack; Xiuxing Wang; Angel M Carcaboso; Andrew E Sloan; Gaoliang Ouyang; Roger E McLendon; Xiu-Wu Bian; Jeremy N Rich; Shideng Bao

doi:10.1084/jem.20151673

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Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitination

Journal article

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Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitination

Xiaoguang Fang, Wenchao Zhou, Qiulian Wu, Zhi Huang, Yu Shi, Kailin Yang, Cong Chen, Qi Xie, Stephen C Mack, Xiuxing Wang, …

The Journal of experimental medicine, Vol.214(1), pp.245-267

01/01/2017

DOI: 10.1084/jem.20151673

PMCID: PMC5206492

PMID: 27923907

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Abstract

Glioblastoma is the most lethal brain tumor and harbors glioma stem cells (GSCs) with potent tumorigenic capacity. The function of GSCs in tumor propagation is maintained by several core transcriptional regulators including c-Myc. c-Myc protein is tightly regulated by posttranslational modification. However, the posttranslational regulatory mechanisms for c-Myc in GSCs have not been defined. In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation. In contrast, overexpression of the ubiquitin E3 ligase FBXL14 induced c-Myc degradation, promoted GSC differentiation, and inhibited tumor growth. Ectopic expression of the ubiquitin-insensitive mutant T58A-c-Myc rescued the effects caused by FBXL14 overexpression or USP13 disruption. These data suggest that USP13 and FBXL14 play opposing roles in the regulation of GSCs through reversible ubiquitination of c-Myc.

Brain Neoplasms - pathology

Cell Line, Tumor

Cell Proliferation

Endopeptidases - physiology

F-Box Proteins - antagonists & inhibitors

F-Box Proteins - physiology

Glioblastoma - pathology

Humans

Neoplastic Stem Cells - pathology

Proto-Oncogene Proteins c-myc - metabolism

Ubiquitin-Protein Ligases - antagonists & inhibitors

Ubiquitin-Protein Ligases - physiology

Ubiquitination

Details

Title: Subtitle: Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitination
Creators: Xiaoguang Fang - Cleveland Clinic Lerner College of Medicine
Wenchao Zhou - Cleveland Clinic Lerner College of Medicine
Qiulian Wu - Cleveland Clinic Lerner College of Medicine
Zhi Huang - Cleveland Clinic Lerner College of Medicine
Yu Shi - Southwest Hospital
Kailin Yang - Cleveland Clinic Lerner College of Medicine
Cong Chen - Southwest Hospital
Qi Xie - Cleveland Clinic Lerner College of Medicine
Stephen C Mack - Cleveland Clinic Lerner College of Medicine
Xiuxing Wang - Cleveland Clinic Lerner College of Medicine
Angel M Carcaboso - Sant Joan de Déu Research Foundation
Andrew E Sloan - Case Western Reserve University
Gaoliang Ouyang - Xiamen University
Roger E McLendon - Duke University Hospital
Xiu-Wu Bian - Southwest Hospital
Jeremy N Rich - Cleveland Clinic Lerner College of Medicine
Shideng Bao - Cleveland Clinic Lerner College of Medicine
Resource Type: Journal article
Publication Details: The Journal of experimental medicine, Vol.214(1), pp.245-267
DOI: 10.1084/jem.20151673
PMID: 27923907
PMCID: PMC5206492
NLM abbreviation: J Exp Med
ISSN: 0022-1007
eISSN: 1540-9538
Grant note: R01 CA184090 / NCI NIH HHS S10 RR031537 / NCRR NIH HHS R01 NS091080 / NINDS NIH HHS R01 NS099175 / NINDS NIH HHS S10 OD018205 / NIH HHS
Language: English
Date published: 01/01/2017
Academic Unit: Radiation Oncology
Record Identifier: 9984696564302771

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