Deubiquitinase USP9X deubiquitinates β-catenin and promotes high grade glioma cell growth
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Bo Yang1,3,*, Shiming Zhang1,*, Zhihao Wang1, Chunxu Yang1, Wen Ouyang1, Fuxiang Zhou1, Yunfeng Zhou1,2, Conghua Xie1,2
1Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuchang District, Wuhan, 430071, China
2Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuchang District, Wuhan, 430071, China
3Department of Oncology, Wuhan General Hospital of Guangzhou Command PLA, Wuchang District, Wuhan, 430070, China
*These authors have contributed equally to this work
Conghua Xie, email: firstname.lastname@example.org
Keywords: high grade gliomas, USP9X, β-catenin, deubiquitination, prognosis
Received: May 12, 2016 Accepted: October 14, 2016 Published: October 22, 2016
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.
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