Aberrant expression of USP22 is associated with liver metastasis and poor prognosis of colorectal cancer

Liu, Yanlong; Yang, Yanmei; Xu, Hui; Xiao, Dong

doi:10.1002/jso.21802

Cited by 92 publications

(98 citation statements)

References 25 publications

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“…Given that USP22 overexpression is correlated with several aggressive cancers (3,16,22), we examined ATXN7L3B protein levels in normal mammary, estrogen receptor-positive (ER ϩ ), and HER2-positive (HER2 ϩ ) breast cancer cell lines (Fig. 6A).…”

Section: Resultsmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

“…Our data provide new insights into ATXN7L3B functions in regulating USP22 activity and localization. Since USP22 overexpression is observed in several highly aggressive cancers (15,16), we also asked whether ATXN7L3B has functions in breast cancer. We found that ATXN7L3B is highly expressed in estrogen receptor-positive (ER ϩ ) breast cancer cell lines.…”

mentioning

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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“…A large body of research has linked this enzyme to tumour progression and oncogenic activity, and USP22 is currently under investigation as a therapeutic target for cancer. Elevated expression has been shown to act as a key indicator of poor prognosis in a variety of different cancers including invasive breast cancer (Zhang et al 2011a), colorectal carcinoma (Liu et al 2011), oesophageal cancer , papillary thyroid carcinoma (Wang et al 2013b), gastric cancer , oral squamous cell carcinoma (Piao et al 2012), salivary duct carcinoma (Piao et al 2013), non-small cell lung carcinoma (Ning et al 2012) and cervical cancer (Yang et al 2014). In addition, inhibition of USP22 has been demonstrated to induce cell cycle arrest and inhibit proliferation in hepatocellular carcinoma (HCC; Ling et al 2012) and bladder cancer (Lv et al 2011).…”

Section: 'Erasing' H2bub1: Dubsmentioning

confidence: 99%

Histone H2B monoubiquitination: roles to play in human malignancy

Cole¹,

Clifton‐Bligh²,

Marsh³

2014

Endocrine-Related Cancer

117

120

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Ubiquitination has traditionally been viewed in the context of polyubiquitination that is essential for marking proteins for degradation via the proteasome. Recent discoveries have shed light on key cellular roles for monoubiquitination, including as a post-translational modification (PTM) of histones such as histone H2B. Monoubiquitination plays a significant role as one of the largest histone PTMs, alongside smaller, better-studied modifications such as methylation, acetylation and phosphorylation. Monoubiquitination of histone H2B at lysine 120 (H2Bub1) has been shown to have key roles in transcription, the DNA damage response and stem cell differentiation. The H2Bub1 enzymatic cascade involves E3 RING finger ubiquitin ligases, with the main E3 generally accepted to be the RNF20-RNF40 complex, and deubiquitinases including ubiquitin-specific protease 7 (USP7), USP22 and USP44. H2Bub1 has been shown to physically disrupt chromatin strands, fostering a more open chromatin structure accessible to transcription factors and DNA repair proteins. It also acts as a recruiting signal, actively attracting proteins with roles in transcription and DNA damage. H2Bub1 also appears to play central roles in histone cross-talk, influencing methylation events on histone H3, including H3K4 and H3K79. Most significantly, global levels of H2Bub1 are low to absent in advanced cancers including breast, colorectal, lung and parathyroid, marking H2Bub1 and the enzymes that regulate it as key molecules of interest as possible new therapeutic targets for the treatment of cancer. This review offers an overview of current knowledge regarding H2Bub1 and highlights links between dysregulation of H2Bub1-associated enzymes, stem cells and malignancy.

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“…Beyond its SAGA-related functions, the study of USP22 has been relatively limited, although several reports have uncovered correlative links to human pathology. For instance, USP22 has been shown to be part of an 11-gene death-from-cancer signature that is predictive of treatment failure (48,49), and its increased expression is associated with a poor prognosis in a variety of cancers (50,51).…”

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confidence: 99%

A High-Confidence Interaction Map Identifies SIRT1 as a Mediator of Acetylation of USP22 and the SAGA Coactivator Complex

Armour

Bennett

Braun

et al. 2013

Molecular and Cellular Biology

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dAlthough many functions and targets have been attributed to the histone and protein deacetylase SIRT1, a comprehensive analysis of SIRT1 binding proteins yielding a high-confidence interaction map has not been established. Using a comparative statistical analysis of binding partners, we have assembled a high-confidence SIRT1 interactome. Employing this method, we identified the deubiquitinating enzyme ubiquitin-specific protease 22 (USP22), a component of the deubiquitinating module (DUBm) of the SAGA transcriptional coactivating complex, as a SIRT1-interacting partner. We found that this interaction is highly specific, requires the ZnF-UBP domain of USP22, and is disrupted by the inactivating H363Y mutation within SIRT1. Moreover, we show that USP22 is acetylated on multiple lysine residues and that alteration of a single lysine (K129) within the ZnF-UBP domain is sufficient to alter interaction of the DUBm with the core SAGA complex. Furthermore, USP22-mediated recruitment of SIRT1 activity promotes the deacetylation of individual SAGA complex components. Our results indicate an important role of SIRT1-mediated deacetylation in regulating the formation of DUBm subcomplexes within the larger SAGA complex.

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Aberrant expression of USP22 is associated with liver metastasis and poor prognosis of colorectal cancer

Abstract: USP22 might be an independent predictive factor for CRC prognosis and aberrant expression of USP22 may play an essential role in colorectal carcinogenesis and liver metastasis.

Cited by 92 publications

References 25 publications

Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module

Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module

Histone H2B monoubiquitination: roles to play in human malignancy

A High-Confidence Interaction Map Identifies SIRT1 as a Mediator of Acetylation of USP22 and the SAGA Coactivator Complex

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