Open AccessUbiquitin‐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
Author(s) -
Qiu GuanZhong,
Mao XiaoYuan,
Ma Yue,
Gao XingChun,
Wang Zhen,
Jin MingZhu,
Sun Wei,
Zou YongXiang,
Lin Jing,
Fu HuaLin,
Jin WeiLin
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13646
Subject(s) - glioma , deubiquitinating enzyme , cancer research , biology , cancer stem cell , gene knockdown , cancer , carcinogenesis , stem cell , ubiquitin , cell culture , microbiology and biotechnology , genetics , gene
Ubiquitin‐specific protease 22 ( USP 22) is a member of the “death‐from‐cancer” signature, which plays a key role in cancer progression. Previous evidence has shown that USP 22 is overexpressed and correlates with poor prognosis in glioma. The effect and mechanism of USP 22 in glioma malignancy, especially cancer stemness, remain elusive. Herein, we find USP 22 is more enriched in stem‐like tumorspheres than differentiated glioma cells. USP 22 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 ( BMI 1), a robust glioma stem‐cell marker, is found to mediate the effect of USP 22 on glioma stemness. By immunofluorescence, USP 22 and BMI 1 are found to share similar intranuclear expression in glioma cells. By analysis with immunohistochemistry and bioinformatics, USP 22 is found to positively correlate with BMI 1 at the post‐translational level only rather than at the transcriptional level. By immunoprecipitation and in vivo deubiquitination assay, USP 22 is found to interact with and deubiquitinate BMI 1 for protein stabilization. Microarray analysis shows that USP 22 and BMI 1 mutually regulate a series of genes involved in glioma stemness such as POSTN , HEY 2 , PDGFRA and ATF 3 . In vivo study with nude mice confirms the role of USP 22 in promoting glioma tumorigenesis by regulating BMI 1. All these findings indicate USP 22 as a novel deubiquitinase of BMI 1 in glioma. We propose a working model of the USP 22‐ BMI 1 axis, which promotes glioma stemness and tumorigenesis through oncogenic activation. Thus, targeting USP 22 might be an effective strategy to treat glioma especially in those with elevated BMI 1 expression.