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Cancer Sci. 2018 Jul;109(7):2199-2210. doi: 10.1111/cas.13646. Epub 2018 Jun 28.

Ubiquitin-specific protease 22 acts as an oncoprotein to maintain glioma malignancy through deubiquitinating B cell-specific Moloney murine leukemia virus integration site 1 for stabilization.

Qiu GZ1,2, Mao XY3,4,5, Ma Y1, Gao XC6, Wang Z1, Jin MZ7, Sun W8, Zou YX8, Lin J9, Fu HL1,10, Jin WL1,10.

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Department of Instrument Science and Engineering, Key Lab. for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Institute of Nano Biomedicine and Engineering, Shanghai Jiao Tong University, Shanghai, China.
Department of Neurosurgery, General Hospital of Jinan Military Command, Jinan, China.
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
Institute of Clinical Pharmacology, Central South University, Changsha, China.
Human Key Laboratory of Pharmacogenetics, Changsha, China.
Shanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic Medical Medicine, Xi'an Medical University, Xi'an, China.
Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
Department of Neurosurgery, The General Hospital of Western Air Force, Chengdu, China.
National Centers for Translational Medicine, Shanghai Jiao Tong University, Shanghai, China.


Ubiquitin-specific protease 22 (USP22) is a member of the "death-from-cancer" signature, which plays a key role in cancer progression. Previous evidence has shown that USP22 is overexpressed and correlates with poor prognosis in glioma. The effect and mechanism of USP22 in glioma malignancy, especially cancer stemness, remain elusive. Herein, we find USP22 is more enriched in stem-like tumorspheres than differentiated glioma cells. USP22 knockdown inhibits cancer stemness in glioma cell lines. With a cell-penetrating TAT-tag protein, B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), a robust glioma stem-cell marker, is found to mediate the effect of USP22 on glioma stemness. By immunofluorescence, USP22 and BMI1 are found to share similar intranuclear expression in glioma cells. By analysis with immunohistochemistry and bioinformatics, USP22 is found to positively correlate with BMI1 at the post-translational level only rather than at the transcriptional level. By immunoprecipitation and in vivo deubiquitination assay, USP22 is found to interact with and deubiquitinate BMI1 for protein stabilization. Microarray analysis shows that USP22 and BMI1 mutually regulate a series of genes involved in glioma stemness such as POSTN, HEY2, PDGFRA and ATF3. In vivo study with nude mice confirms the role of USP22 in promoting glioma tumorigenesis by regulating BMI1. All these findings indicate USP22 as a novel deubiquitinase of BMI1 in glioma. We propose a working model of the USP22-BMI1 axis, which promotes glioma stemness and tumorigenesis through oncogenic activation. Thus, targeting USP22 might be an effective strategy to treat glioma especially in those with elevated BMI1 expression.


BMI1; USP22; cancer stemness; deubiquitination; glioma

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