USP22 maintains gastric cancer stem cell stemness and promotes gastric cancer progression by stabilizing BMI1 protein

Ma, Yue; Fu, Hualin; Wang, Zhen; Huang, Hai; Ni, Jian; Song, Jie; Xia, Ying; Jin, Weilin; Cui, Daxiang

doi:10.18632/oncotarget.16445

Cited by 34 publications

(29 citation statements)

References 65 publications

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“…Therefore, we explored the roles of USP22 in USP22-overexpressing SGC7901 cells and USP22-silenced AGS cells. USP22 promotes cell proliferation, migration, and invasion in multiple cancers, including glioma, lung adenocarcinoma, thyroid carcinoma, colorectal cancer, and gastric cancer [27][28][29][30][31]. Consistent with these findings, our data demonstrate that USP22 promotes gastric cancer cell proliferation, migration, and invasion in vitro and enhances tumor growth in vivo.…”

Section: Discussionsupporting

confidence: 87%

Ubiquitin-specific peptide 22 acts as an oncogene in gastric cancer in a son of sevenless 1-dependent manner

Lim

Chen

et al. 2020

Cancer Cell Int

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Background: Aberrant expression of ubiquitin-specific peptide 22 (USP22) has been detected in various cancers. This study aimed to investigate the role of USP22 and the underlying mechanism in human gastric cancer. Methods:The expression pattern of USP22 in human gastric cancer was detected in a tissue microarray containing 88 pairs of gastric cancer tissue and adjacent normal tissue samples from patients with primary gastric cancer using immunohistochemical staining. The correlation of USP22 expression with clinical characteristics of patients, as well as their prognostic values in the overall survival of patients, were evaluated. USP22-overexpressing SGC7901 and USP22-silencing AGS cells were used to explore the role of USP22 in gastric cancer cell behavior in vitro and in vivo. Chromatin immunoprecipitation was performed to identify differentially expressed genes induced by USP22 overexpression. Western blot analysis was conducted to detect the activation of RAS/ERK and PI3K/AKT signaling in USP22overexpressing SGC7901 cells and xenograft tumor tissues. Knockdown of RAS activator son of sevenless 1 (SOS1) was performed to investigate the role of SOS1 in USP22-regulated gastric cancer cell behavior and RAS signaling both in vitro and in vivo.Results: USP22 protein expression was significantly increased in human gastric cancer tissues, compared with adjacent normal tissues, and was positively correlated with local tumor stage. Gain-and loss-of-function assays showed that USP22 promoted gastric cancer cell growth and cell cycle transition while suppressing apoptosis in vitro. Consistent results were observed in a xenograft mouse model. Chromatin immunoprecipitation revealed that the overexpression of USP22 induced the upregulation of RAS activator son of sevenless 1 (SOS1) in SGC7901 cells. Western blot analysis showed that USP22 overexpression also induced activation of the RAS/ERK and PI3K/AKT pathways in SGC7901 cells and xenograft tumor tissues. Furthermore, SOS1 silencing could reverse the effects of USP22 on gastric cancer cell behavior and RAS signaling both in vitro and in vivo. Conclusions:Our results suggest that USP22 acts as an oncogene in gastric cancer in a SOS1-dependent manner, identifying the USP22/SOS1/RAS axis as a potential therapeutic target in gastric cancer.

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Section: Discussionsupporting

confidence: 87%

Ubiquitin-specific peptide 22 acts as an oncogene in gastric cancer in a son of sevenless 1-dependent manner

Lim

Chen

et al. 2020

Cancer Cell Int

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“…The ubiquitin hydrolase USP22 has been causally linked to aggressive growth in human tumor cells in vitro and in vivo ( 1 , 8 – 13 , 19 – 25 ). Consistent with this, depletion of USP22 in the nonsmall-cell lung cancer line H1299 results in a marked decrease in cell number ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Control of CCND1 ubiquitylation by the catalytic SAGA subunit USP22 is essential for cell cycle progression through G1 in cancer cells

Gennaro

Stanek

Peck

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

100

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SignificanceThe deubiquitylase USP22 is frequently overexpressed in cancer and contributes to tumorigenesis by driving cell cycle progression. Current models define USP22 as functional mediator of gene regulation and chromatin modification, working within the SAGA transcriptional cofactor complex. Here we report a catalytic role for USP22 distinct from its well-characterized transcription regulatory capacity. USP22 directly stabilizes the essential G1-cyclin, CCND1, protecting it from proteasome-mediated degradation via deubiquitylation. Our findings reveal a pathway that regulates CCND1, while also raising the possibility that simulteously targeting USP22 may allow the use of less toxic doses of the new wave of cancer therapies that target the cyclin/CDK complex. Finally, these results provide a mechanistic explanation for the effects of USP22 in cancer cell cycle control.

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“…We uncover a USP22‐BMI1 axis, which promotes glioma malignancy through oncogenic activation of a series of gene targets. Considering BMI1 regulation by USP22 in other malignancies, we speculate a common existence of the USP22‐BMI1 axis in cancers. Hence, targeting the USP22‐BMI1 axis may not only be a promising alternative approach to treat glioma, but may also be used to treat other types of cancer.…”

Section: Discussionmentioning

confidence: 83%

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

Mao

et al. 2018

Cancer Science

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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.

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USP22 maintains gastric cancer stem cell stemness and promotes gastric cancer progression by stabilizing BMI1 protein

Cited by 34 publications

References 65 publications

Ubiquitin-specific peptide 22 acts as an oncogene in gastric cancer in a son of sevenless 1-dependent manner

Ubiquitin-specific peptide 22 acts as an oncogene in gastric cancer in a son of sevenless 1-dependent manner

Control of CCND1 ubiquitylation by the catalytic SAGA subunit USP22 is essential for cell cycle progression through G1 in cancer cells

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

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