USP22 promotes the G1/S phase transition by upregulating FoxM1 expression via β-catenin nuclear localization and is associated with poor prognosis in stage II pancreatic ductal adenocarcinoma

Zhang, Ning; Wang, Aman; Liang, Jinxiao; Xie, Yuanfang; LIU, JIWEI; Feng, Liang; Qiu, Yan; WANG, ZHONGYU

doi:10.3892/ijo.2014.2531

Cited by 52 publications

(48 citation statements)

References 66 publications

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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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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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“…Because USP22 is functionally correlated with Wnt/β-catenin signaling regulators and proteins Foxm1 and GSKβ [7, 16], we hypothesized that USP22 maintains CRC cell stemness and tumorigenesis through Wnt/β-catenin signaling. To explore this hypothesis, we performed RT-PCR and western blot assays for Wnt/β-catenin signaling target genes (Axin2, MYC and Cyclin D1) in USP22 knockdown Caco2 and HCT15 stem cells.…”

Section: Resultsmentioning

confidence: 99%

“…It has been shown to promote cell cycle progression and tumorigenesis [7-9]. Furthermore, USP22 expression correlates with CRC progression and therapy failure [10].…”

Section: Introductionmentioning

confidence: 99%

“…Increased Wnt signaling indicates a poor prognosis for patients with CRC, and disrupting Wnt pathway activation prevents CRC progression [15]. Given the evidence for USP22's promotion of β-catenin nuclear localization, which is necessary for Wnt pathway activation, we hypothesized that USP22 maintains CRC cell stemness and tumorigenesis through Wnt/β-catenin signaling [7]. USP22 knockdown in CRC cell lines does in fact reduce Wnt/β-catenin signaling, suggesting a greater role for USP22 in CRC progression than was previously supposed.…”

Section: Introductionmentioning

confidence: 99%

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Ubiquitin-Specific Peptidase 22 Contributes to Colorectal Cancer Stemness and Chemoresistance via Wnt/β-Catenin Pathway

Jiang

Song

et al. 2018

Cell Physiol Biochem

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Background/Aims: Two major barriers to the successful treatment of colorectal cancer (CRC) are the development of stem cell-like characteristics (stemness) and chemoresistance. Ubiquitin-specific peptidase 22 (USP22) is a deubiquitinating enzyme and putative CRC marker that has emerged as a potential cause of both phenomena in CRC. There is evidence that USP22 acts through the Wnt/β-catenin pathway and that downregulation of the latter may reduce chemoresistance. Methods: In this study, we used CRC tissue specimens from human patients as well as human CRC cell lines to evaluate the role of USP22 in CRC stemness and chemoresistance in vitro and in vivo. RT-PCR and western blot were used for gene expression analyses. Immunohistochemistry was performed for USP22 expression in clinical samples. CD133 levels were analyzed by flow cytometry. Sphere formation and MTT assays were used for self-renewal and proliferation analysis. Chemoresistance was evaluated by cell viability and sphere formation assays. Results: We found a significant increase of USP22 in recurrent CRC and chemoresistant CRC cells as compared to primary CRC and non-chemoresistant CRC cells, respectively. We then demonstrated that USP22 mediates CRC cell chemoresistance through the Wnt/β-catenin pathway and that reducing USP22 in CRC cells diminishes chemoresistance. Conclusions: Having established the crucial role of USP22 in CRC stemness and chemoresistance, this study suggests that USP22 may be an ideal genetic target in the treatment of chemoresistant CRC.

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“…Previous studies have indicated that, during the embryonic period, FOXM1 is overexpressed in all tissues (15); however, in adulthood, FOXM1 expression only occurs in the tissues with active proliferation and metabolism (16). In various types of tumor cells, FOXM1 is highly expressed in the nucleus and cytoplasm, and causes the dysfunction of regulation processes (17)(18)(19)(20)(21). In particular, FOXM1 controls mitotic entry by the periodic upregulation of a group of genes that are maximally expressed as cells progress through the late G2 and into the M phase (14).…”

Section: Introductionmentioning

confidence: 99%

FOXM1 participates in PLK1-regulated cell cycle progression in renal cell cancer cells

Zhang

Kong

2016

Oncology Letters

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Abstract. The regulation of entry into and progression through mitosis is important for cell proliferation. Polo-like kinase 1 (PLK1) is involved in multiple stages of mitosis. Forkhead box protein M1 (FOXM1) has multiple functions in tumorigenesis and, in elevated levels, is frequently associated with cancer progression. The present study reports that FOXM1, a substrate of PLK1, controls the transcription mechanism that mediates the PLK1-dependent regulation of the cell cycle. The present study investigated the expression of PLK1 and FOXM1 in the clear renal cell carcinoma 769-P and ACHN cell lines, and indicated that the expression of PLK1 and FOXM1 are correlated in human renal cell cancer cell lines and that the suppression of PLK1 may decrease the expression of FOXM1. The knockdown of FOXM1 or PLK1 in renal cell cancer cell lines caused cell cycle progression to be blocked. As a result, the present study indicated the involvement of FOXM1 in PLK1-regulated cell cycle progression.

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USP22 promotes the G1/S phase transition by upregulating FoxM1 expression via β-catenin nuclear localization and is associated with poor prognosis in stage II pancreatic ductal adenocarcinoma

Cited by 52 publications

References 66 publications

Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module

Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module

Ubiquitin-Specific Peptidase 22 Contributes to Colorectal Cancer Stemness and Chemoresistance via Wnt/β-Catenin Pathway

FOXM1 participates in PLK1-regulated cell cycle progression in renal cell cancer cells

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