Ubiquitin-specific peptidase 22 overexpression may promote cancer progression and poor prognosis in human gastric carcinoma

He, Yan; Jin, Yinji; Zhang, Yuhua; Meng, Hongxue; Zhao, Baoshan; Jiang, Yang; Zhu, Jiwei; Liang, Guan-Ying; Kong, Dan; Jin, Xiaoming

doi:10.1016/j.trsl.2014.09.005

Cited by 22 publications

(21 citation statements)

References 24 publications

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“…Increasing evidence has shown that the USP family members are differentially expressed or elevated in tumors, indicating they are potential therapeutic targets in cancer treatment [34–38]. Although USP22 was reported as a “death-from-cancer” signature and was aberrantly increased in many cancers, the molecular mechanisms underlying the elevated expression of USP22 during GC progression and poor prognosis are still elusive [39–41]. Here, we found that USP22 is highly overexpressed in GC and positively associated with BMI1.…”

Section: Discussionmentioning

confidence: 99%

“…GCN5 was shown to be required for SAGA to activate c-Myc target genes and promotes non-small cell lung cancer, glioma and hepatocellular carcinoma progression [43–46]. USP22 was also identified as an oncogene and associated with many cancers, such as colorectal cancer, breast cancer, oral squamous cell carcinoma, anaplastic thyroid carcinoma, glioma and GC [25, 41, 47–49]. …”

Section: Discussionmentioning

confidence: 99%

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

Wang

et al. 2017

Oncotarget

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Increased ubiquitin-specific protease 22 (USP22) has been associated with poor prognosis in several cancers including gastric cancer. However, the role of USP22 in gastric tumorigenesis is still unclear. Gastric cancer stem cells have been identified and shown to correlate with gastric cancer initiation and metastasis. In this study, we found that silencing of USP22 inhibited proliferation of gastric cancer cells and suppressed the cancer stem cell spheroid formation in serum-free culture. Furthermore, cancer stem cell markers, such as CD133, SOX2, OCT4 and NANOG were down-regulated. Additionally, knockdown of USP22 inhibited gastric cancer xenografts growth. Our analysis of TCGA database indicated that BMI1 overexpression may predict gastric cancer patient survival, and TAT-BMI1 proteins reversed the USP22 knockdown-mediated decreased in cancer stem cell properties, and elevated the expression of stemness-associated genes. Furthermore, we found that overexpression of USP22 stabilized the BMI1 protein in gastric cancer cells. Taken together, our study demonstrates that USP22 is indispensable for gastric cancer stem cell self-renewal through stabilization of BMI1. These results may provide novel approaches to the theranostics of gastric cancer in the near future.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Wang

et al. 2017

Oncotarget

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“…As early as 2005, USP22 was identified as a member of an 11-gene "deathfrom-cancer" signature for highly aggressive tumors (15). Elevated expression of USP22 has since been reported to be a prognostic factor for poor survival in patients with colorectal cancer (16), breast cancer (22), pancreatic cancer (26,27), cervical cancer (28), oral squamous cell carcinoma (29), hepatocellular carcinoma (30), and gastric carcinoma (31).…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module

Atanassov

Lan

et al. 2016

Molecular and Cellular Biology

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fThe SAGA complex contains two enzymatic modules, which house histone acetyltransferase (HAT) and deubiquitinase (DUB) activities. USP22 is the catalytic subunit of the DUB module, but two adaptor proteins, ATXN7L3 and ENY2, are necessary for DUB activity toward histone H2Bub1 and other substrates. ATXN7L3B shares 74% identity with the N-terminal region of ATXN7L3, but the functions of ATXN7L3B are not known. Here we report that ATXN7L3B interacts with ENY2 but not other SAGA components. Even though ATXN7L3B localizes in the cytoplasm, ATXN7L3B overexpression increases H2Bub1 levels, while overexpression of ATXN7L3 decreases H2Bub1 levels. In vitro, ATXN7L3B competes with ATXN7L3 to bind ENY2, and in vivo, knockdown of ATXN7L3B leads to concomitant loss of ENY2. Unlike the ATXN7L3 DUB complex, a USP22-ATXN7L3B-ENY2 complex cannot deubiquitinate H2Bub1 efficiently in vitro. Moreover, ATXN7L3B knockdown inhibits migration of breast cancer cells in vitro and limits expression of ER target genes. Collectively, our studies suggest that ATXN7L3B regulates H2Bub1 levels and SAGA DUB activity through competition for ENY2 binding. U SP22 and the SAGA deubiquitinase (DUB) module are important for normal embryonic development (1), and alterations in the expression or structure of component proteins are linked to neurodegenerative disease and cancer (2, 3). The DUB module consists of a catalytic subunit, USP22, and two adaptor proteins, ATXN7L3 and ENY2, required for deubiquitinase activity and stability of the DUB module (4-6). Another protein, ATXN7, functions as a bridge to integrate the core DUB module into the greater SAGA complex (7,8) and has also been reported to affect DUB activity (6, 9, 10).ATXN7L3 contains a Sus1/ENY2-binding region in its N-terminal region, a ZnF-Sgf11 domain, and a SCA7 domain in its C-terminal region (6). The presence of ATXN7L3 is essential for the deubiquitinase activity of the DUB module. No stable complex could be formed in the absence of ATXN7L3 (6). Moreover, the ZnF-Sgf11 domain of ATXN7L3 plays a pivotal role in the enzymatic activity, but is dispensable for the assembly, of the DUB module (6). The ZnF-Sgf11 domain of ATXN7L3 is essential for DUB activity toward H2Bub1 in vitro (6). The ZnF-Sgf11 domain is required for ATXN7L3 binding to nucleosomal DNA (11), and the crystal structure of the DUB module reveals that an arginine cluster in the ZnF-Sgf11 domain directly interacts with ubiquitinated nucleosomes and H2A/H2B heterodimer (12).Loss of ATXN7L3B, a paralog of ATXN7L3, may also be associated with neurodegenerative disease (13), as three family members exhibiting loss of chromosome region 12q21, where ATXN7L3B lies, exhibited motor and cognitive deficiencies, as well as learning difficulties and cerebellar ataxia. ATXN7L3B and ATXN7L3 share 74% identity within their N-terminal ϳ60 amino acid residues (Fig. 1A), including the Sus1/ENY2-binding region (Fig. 1A, in red) (6, 14). Interestingly, a truncated form of ATXN7L3 that only contains amino acids 3 to 76 was shown by others to ...

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“…Several reports indicate that USP22 overexpression is linked to unfavorable outcomes in multiple types of cancers (He et al, 2015; Liang et al, 2014; Ning et al, 2012; Zhang et al, 2011). However, the mechanisms underlying USP22 overexpression in different malignancies and molecular links between histone deubiquitination and aggressive tumor growth are still not clear.…”

Section: Introductionmentioning

confidence: 99%

ATXN7L3 and ENY2 Coordinate Activity of Multiple H2B Deubiquitinases Important for Cellular Proliferation and Tumor Growth

et al. 2016

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SUMMARY Histone H2B monoubiquitination (H2Bub1) is centrally involved in gene regulation. The deubiquitination module (DUBm) of the SAGA complex is a major regulator of global H2Bub1 levels, and components of this DUBm are linked to both neurodegenerative diseases and cancer. Unexpectedly, we find that ablation of USP22, the enzymatic center of the DUBm, leads to a reduction, rather than an increase, in global H2bub1 levels. In contrast, depletion of non-enzymatic components, ATXN7L3 or ENY2, results in increased H2Bub1. These observations led us to discover two new H2Bub1 DUBs, USP27X and USP51, which function independently of SAGA and which compete with USP22 for ATXN7L3 and ENY2 for activity. Like USP22, USP51 and USP27X are required for normal cell proliferation, and their depletion suppresses tumor growth. Our results reveal that ATXN7L3 and ENY2 orchestrate activities of multiple deubiquitinating enzymes and that imbalances in these activities likely potentiate human diseases including cancer.

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Ubiquitin-specific peptidase 22 overexpression may promote cancer progression and poor prognosis in human gastric carcinoma

Cited by 22 publications

References 24 publications

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

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

Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module

ATXN7L3 and ENY2 Coordinate Activity of Multiple H2B Deubiquitinases Important for Cellular Proliferation and Tumor Growth

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