title: Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitination.
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.
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Xiaoguang
authors.identifier: 0000-0002-3368-4133
authors.initials: X
authors.lastname: Fang
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Qiulian
authors.identifier: 0000-0002-2040-4577
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Zhi
authors.identifier: 0000-0002-8658-7732
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.|Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
authors.forename: Yu
authors.identifier: 0000-0002-3380-4545
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Kailin
authors.identifier: 0000-0001-5968-6738
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.|Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
authors.forename: Cong
authors.identifier: 0000-0001-6552-791X
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Qi
authors.identifier: 0000-0002-2370-2078
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Mack
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Xiuxing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Preclinical Therapeutics and Drug Delivery Research Program, Fundacio Sant Joan de Deu, 08950 Barcelona, Spain.
authors.forename: Angel M
authors.identifier: 0000-0002-8485-426X
authors.initials: AM
authors.lastname: Carcaboso
authors.affiliation: Department of Neurological Surgery, University Hospitals, Case Western Reserve University School of Medicine, Cleveland, OH 44106.|Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors.forename: Andrew E
authors.identifier: 0000-0001-9607-5063
authors.initials: AE
authors.lastname: Sloan
authors.affiliation: The State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China.
authors.forename: Gaoliang
authors.initials: G
authors.lastname: Ouyang
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Roger E
authors.identifier: 0000-0001-6682-4588
authors.initials: RE
authors.lastname: McLendon
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
authors.forename: Xiu-Wu
authors.initials: XW
authors.lastname: Bian
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195 baos@ccf.org richj@ccf.org.|Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195 baos@ccf.org richj@ccf.org.|Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors.forename: Shideng
authors.identifier: 0000-0002-4236-2662
authors.initials: S
authors.lastname: Bao
mesh_terms: D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D010450:Endopeptidases / Q000502:physiology*; D044783:F-Box Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000502:physiology; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination
chemical_list: D044783:F-Box Proteins; C547521:FBXL14 protein, human; D016271:Proto-Oncogene Proteins c-myc; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; C561638:USP13 protein, human; D064570:Ubiquitin-Specific Proteases