title: Deubiquitinase USP9X deubiquitinates β-catenin and promotes high grade glioma cell growth.
abstract: β-catenin is a crucial signal transduction molecule in the Wnt/β-catenin signal pathway, and increased β-catenin expression has consistently been found in high grade gliomas. However, the mechanisms responsible for β-catenin overexpression have remained elusive.Here we show that the deubiquitinase USP9X stabilizes β-catenin and thereby promotes high grade glioma cell growth. USP9X binds β-catenin and removes the Lys 48-linked polyubiquitin chains that normally mark β-catenin for proteasomal degradation. Increased USP9X expression correlates with increased β-catenin protein in high grade glioma tissues. Moreover, patients with high grade glioma overexpressing USP9X have a poor prognosis. Knockdown of USP9X suppresses cell proliferation, inhibits G1/S phase conversion, and induces apoptosis in U251 and A172 cells. Interestingly, c-Myc and cyclinD1, which are important downstream target genes in the Wnt/β-catenin signal pathway, also show decreased expression in cells with siRNA-mediated down-regulation of USP9X. Down-regulation of USP9X also consistently inhibits the tumorigenicity of primary glioma cells in vivo.In summary, these results indicate that USP9X stabilizes β-catenin and activates Wnt/β-catenin signal pathway to promote glioma cell proliferation and survival. USP9X could also potentially be a novel therapeutic target for high grade gliomas.
authors: Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuchang District, Wuhan, 430071, China.|Department of Oncology, Wuhan General Hospital of Guangzhou Command PLA, Wuchang District, Wuhan, 430070, China.
authors: Bo
authors: B
authors: Yang
authors: Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuchang District, Wuhan, 430071, China.
authors: Shiming
authors: S
authors: Zhang
authors: Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuchang District, Wuhan, 430071, China.
authors: Zhihao
authors: Z
authors: Wang
authors: Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuchang District, Wuhan, 430071, China.
authors: Chunxu
authors: C
authors: Yang
authors: Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuchang District, Wuhan, 430071, China.
authors: Wen
authors: W
authors: Ouyang
authors: Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuchang District, Wuhan, 430071, China.
authors: Fuxiang
authors: F
authors: Zhou
authors: Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuchang District, Wuhan, 430071, China.|Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuchang District, Wuhan, 430071, China.
authors: Yunfeng
authors: Y
authors: Zhou
authors: Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuchang District, Wuhan, 430071, China.|Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuchang District, Wuhan, 430071, China.
authors: Conghua
authors: C
authors: Xie
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004795:Enzyme Stability; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D060787:Neoplasm Grading; D016016:Proportional Hazards Models; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D060449:Wnt Signaling Pathway; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C530104:CCND1 protein, human; C495270:CTNNB1 protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C506234:USP9X protein, human; D051176:beta Catenin; D019938:Cyclin D1; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex
keywords: USP9X; deubiquitination; high grade gliomas; prognosis; β-catenin