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USP9X deubiquitinates ALDH1A3 and maintains mesenchymal identity in glioblastoma stem cells
- Source :
- J Clin Invest
- Publication Year :
- 2019
- Publisher :
- American Society for Clinical Investigation, 2019.
-
Abstract
- The mesenchymal (MES) subtype of glioblastoma (GBM) stem cells (GSCs) represents a subpopulation of cancer cells that are notorious for their highly aggressive nature and resistance to conventional therapy. Aldehyde dehydrogenase 1A3 (ALDH1A3) has been recently suggested as a key determinant for the maintenance of MES features of GSCs. However, the mechanisms underpinning aberrant ALDH1A3 expression remain elusive. Here, we identified ubiquitin-specific protease 9X (USP9X) as a bona fide deubiquitinase of ALDH1A3 in MES GSCs. USP9X interacted with, depolyubiquitylated, and stabilized ALDH1A3. Moreover, we showed that FACS-sorted USP9X(hi) cells were enriched for MES GSCs with high ALDH1A3 activity and potent tumorigenic capacity. Depletion of USP9X markedly downregulated ALDH1A3, resulting in a loss of self-renewal and tumorigenic capacity of MES GSCs, which could be largely rescued by ectopic expression of ALDH1A3. Furthermore, we demonstrated that the USP9X inhibitor WP1130 induced ALDH1A3 degradation and showed marked therapeutic efficacy in MES GSC–derived orthotopic xenograft models. Additionally, USP9X strongly correlated with ALDH1A3 expression in primary human GBM samples and had a prognostic value for patients with the MES subgroup. Collectively, our findings unveil USP9X as a key deubiquitinase for ALDH1A3 protein stabilization and a potential target for GSC-directed therapy.
- Subjects :
- 0301 basic medicine
endocrine system
animal structures
Carcinogenesis
Aldehyde dehydrogenase
Cell Separation
Deubiquitinating enzyme
Mice
03 medical and health sciences
0302 clinical medicine
Catalytic Domain
Cell Line, Tumor
Animals
Humans
RNA, Small Interfering
Microscopy, Confocal
biology
Ubiquitin
Brain Neoplasms
Mesenchymal stem cell
Mesenchymal Stem Cells
General Medicine
Aldehyde Dehydrogenase
Flow Cytometry
Prognosis
Aldehyde Oxidoreductases
Gene Expression Regulation, Neoplastic
HEK293 Cells
030104 developmental biology
USP9X
Immunoglobulin G
030220 oncology & carcinogenesis
Cancer cell
Commentary
Neoplastic Stem Cells
biology.protein
Cancer research
Ectopic expression
Stem cell
Protein stabilization
Glioblastoma
Ubiquitin Thiolesterase
Neoplasm Transplantation
Research Article
Subjects
Details
- ISSN :
- 15588238 and 00219738
- Volume :
- 129
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....4bc53fcbbcc9111c2742866d64262bd4
- Full Text :
- https://doi.org/10.1172/jci126414