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: 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
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 214 Issue 1 Pg. 245-267 (01 2017) ISSN: 1540-9538 [Electronic] United States
• PMID: 27923907 (Publication Type: Journal Article)
• Copyright: © 2017 Fang et al.

Chemical References

• F-Box Proteins
• FBXL14 protein, human
• Proto-Oncogene Proteins c-myc
• Ubiquitin-Protein Ligases
• Endopeptidases
• USP13 protein, human
• Ubiquitin-Specific Proteases

Topics

• Brain Neoplasms (pathology)
• Cell Line, Tumor
• Cell Proliferation
• Endopeptidases (physiology)
• F-Box Proteins (antagonists & inhibitors, physiology)
• Glioblastoma (pathology)
• Humans
• Neoplastic Stem Cells (pathology)
• Proto-Oncogene Proteins c-myc (metabolism)
• Ubiquitin-Protein Ligases (antagonists & inhibitors, physiology)
• Ubiquitin-Specific Proteases
• Ubiquitination