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Luo S, Zhang Z, Wang Z, Yang X, Chen X, Zhou T, Zhang J. Inferring transcriptional bursting kinetics from single-cell snapshot data using a generalized telegraph model. ROYAL SOCIETY OPEN SCIENCE 2023; 10:221057. [PMID: 37035293 PMCID: PMC10073913 DOI: 10.1098/rsos.221057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 03/13/2023] [Indexed: 06/19/2023]
Abstract
Gene expression has inherent stochasticity resulting from transcription's burst manners. Single-cell snapshot data can be exploited to rigorously infer transcriptional burst kinetics, using mathematical models as blueprints. The classical telegraph model (CTM) has been widely used to explain transcriptional bursting with Markovian assumptions. However, growing evidence suggests that the gene-state dwell times are generally non-exponential, as gene-state switching is a multi-step process in organisms. Therefore, interpretable non-Markovian mathematical models and efficient statistical inference methods are urgently required in investigating transcriptional burst kinetics. We develop an interpretable and tractable model, the generalized telegraph model (GTM), to characterize transcriptional bursting that allows arbitrary dwell-time distributions, rather than exponential distributions, to be incorporated into the ON and OFF switching process. Based on the GTM, we propose an inference method for transcriptional bursting kinetics using an approximate Bayesian computation framework. This method demonstrates an efficient and scalable estimation of burst frequency and burst size on synthetic data. Further, the application of inference to genome-wide data from mouse embryonic fibroblasts reveals that GTM would estimate lower burst frequency and higher burst size than those estimated by CTM. In conclusion, the GTM and the corresponding inference method are effective tools to infer dynamic transcriptional bursting from static single-cell snapshot data.
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Affiliation(s)
- Songhao Luo
- Guangdong Province Key Laboratory of Computational Science, Sun Yat-sen University, Guangzhou, Guangdong Province 510275, People's Republic of China
- School of Mathematics, Sun Yat-sen University, Guangzhou, Guangdong Province 510275, People's Republic of China
| | - Zhenquan Zhang
- Guangdong Province Key Laboratory of Computational Science, Sun Yat-sen University, Guangzhou, Guangdong Province 510275, People's Republic of China
- School of Mathematics, Sun Yat-sen University, Guangzhou, Guangdong Province 510275, People's Republic of China
| | - Zihao Wang
- Guangdong Province Key Laboratory of Computational Science, Sun Yat-sen University, Guangzhou, Guangdong Province 510275, People's Republic of China
- School of Mathematics, Sun Yat-sen University, Guangzhou, Guangdong Province 510275, People's Republic of China
| | - Xiyan Yang
- School of Financial Mathematics and Statistics, Guangdong University of Finance, Guangzhou 510521, People's Republic of China
| | - Xiaoxuan Chen
- Guangdong Province Key Laboratory of Computational Science, Sun Yat-sen University, Guangzhou, Guangdong Province 510275, People's Republic of China
- School of Mathematics, Sun Yat-sen University, Guangzhou, Guangdong Province 510275, People's Republic of China
| | - Tianshou Zhou
- Guangdong Province Key Laboratory of Computational Science, Sun Yat-sen University, Guangzhou, Guangdong Province 510275, People's Republic of China
- School of Mathematics, Sun Yat-sen University, Guangzhou, Guangdong Province 510275, People's Republic of China
| | - Jiajun Zhang
- Guangdong Province Key Laboratory of Computational Science, Sun Yat-sen University, Guangzhou, Guangdong Province 510275, People's Republic of China
- School of Mathematics, Sun Yat-sen University, Guangzhou, Guangdong Province 510275, People's Republic of China
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Sun N, Zhong X, Wang S, Zeng K, Sun H, Sun G, Zou R, Liu W, Liu W, Lin L, Song H, Lv C, Wang C, Zhao Y. ATXN7L3 positively regulates SMAD7 transcription in hepatocellular carcinoma with growth inhibitory function. EBioMedicine 2020; 62:103108. [PMID: 33186807 PMCID: PMC7670205 DOI: 10.1016/j.ebiom.2020.103108] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 09/11/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, with unmet need for the pharmacological therapy. The functions of ATXN7L3 in HCC progression are not known. Methods RNA sequence, quantitative real-time PCR, and western blot were performed to detect gene expression. Chromatin immunoprecipitation was performed to detect possible mechanisms. Immunohistochemical stain was performed to examine the protein expression. Colony formation, cell growth curve and xenograft tumor experiments were performed to examine cell growth in vitro and in vivo. Findings ATXN7L3 functions as a coactivator for ERα-mediated transactivation in HCC cells, thereby contributing to enhanced SMAD7 transcription. ATXN7L3 is recruited to the promoter regions of SMAD7 gene, thereby regulating histone H2B ubiquitination level, to enhance the transcription of SMAD7. A series of genes regulated by ATXN7L3 were identified. Moreover, ATXN7L3 participates in suppression of tumor growth. In addition, ATXN7L3 is lower expressed in HCC samples, and the lower expression of ATXN7L3 positively correlates with poor clinical outcome in patients with HCC. Interpretation This study demonstrated that ATXN7L3 is a novel regulator of SMAD7 transcription, subsequently participating in inhibition of tumor growth in HCC, which provides an insight to support a previously unknown role of ATXN7L3 in HCC progression. Fund This work was funded by 973 Program Grant from the Ministry of Science and Technology of China (2013CB945201), National Natural Science Foundation of China (31871286, 81872015, 31701102, 81702800, 81902889), Foundation for Special Professor of Liaoning Province, Natural Science Foundation of Liaoning Province (No.20180530072); China Postdoctoral Science Foundation (2019M651164).
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Affiliation(s)
- Ning Sun
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Xinping Zhong
- Department of General Surgery, the First Affiliated Hospital of China Medical University, Shenyang City, Liaoning Province, 110001, China
| | - Shengli Wang
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Kai Zeng
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Hongmiao Sun
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Ge Sun
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Renlong Zou
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Wei Liu
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Wensu Liu
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Lin Lin
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Huijuan Song
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Chi Lv
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China; Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang City, Liaoning Province, 110004, China
| | - Chunyu Wang
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China.
| | - Yue Zhao
- Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China; Department of Endocrinology and Metabolism, Institute of Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang City, Liaoning Province 110001, China.
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Nuño-Cabanes C, García-Molinero V, Martín-Expósito M, Gas ME, Oliete-Calvo P, García-Oliver E, de la Iglesia-Vayá M, Rodríguez-Navarro S. SAGA-CORE subunit Spt7 is required for correct Ubp8 localization, chromatin association and deubiquitinase activity. Epigenetics Chromatin 2020; 13:46. [PMID: 33115507 PMCID: PMC7594455 DOI: 10.1186/s13072-020-00367-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 10/15/2020] [Indexed: 02/07/2023] Open
Abstract
Background Histone H2B deubiquitination is performed by numerous deubiquitinases in eukaryotic cells including Ubp8, the catalytic subunit of the tetrameric deubiquitination module (DUBm: Ubp8; Sus1; Sgf11; Sgf73) of the Spt-Ada-Gcn5 acetyltransferase (SAGA). Ubp8 is linked to the rest of SAGA through Sgf73 and is activated by the adaptors Sus1 and Sgf11. It is unknown if DUBm/Ubp8 might also work in a SAGA-independent manner. Results Here we report that a tetrameric DUBm is assembled independently of the SAGA–CORE components SPT7, ADA1 and SPT20. In the absence of SPT7, i.e., independent of the SAGA complex, Ubp8 and Sus1 are poorly recruited to SAGA-dependent genes and to chromatin. Notably, cells lacking Spt7 or Ada1, but not Spt20, show lower levels of nuclear Ubp8 than wild-type cells, suggesting a possible role for SAGA–CORE subunits in Ubp8 localization. Last, deletion of SPT7 leads to defects in Ubp8 deubiquitinase activity in in vivo and in vitro assays. Conclusions Collectively, our studies show that the DUBm tetrameric structure can form without a complete intact SAGA–CORE complex and that it includes full-length Sgf73. However, subunits of this SAGA–CORE influence DUBm association with chromatin, its localization and its activity.
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Affiliation(s)
- Carme Nuño-Cabanes
- Gene Expression and RNA Metabolism Laboratory, Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas (CSIC), C/Jaume Roig 11, 46010, Valencia, Spain.,Gene Expression and RNA Metabolism Laboratory, Centro de Investigación Príncipe Felipe (CIPF), C/E. Primo Yúfera 3, 46012, Valencia, Spain
| | - Varinia García-Molinero
- Gene Expression and RNA Metabolism Laboratory, Centro de Investigación Príncipe Felipe (CIPF), C/E. Primo Yúfera 3, 46012, Valencia, Spain
| | - Manuel Martín-Expósito
- Gene Expression and RNA Metabolism Laboratory, Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas (CSIC), C/Jaume Roig 11, 46010, Valencia, Spain.,Gene Expression and RNA Metabolism Laboratory, Centro de Investigación Príncipe Felipe (CIPF), C/E. Primo Yúfera 3, 46012, Valencia, Spain
| | - María-Eugenia Gas
- Gene Expression and RNA Metabolism Laboratory, Centro de Investigación Príncipe Felipe (CIPF), C/E. Primo Yúfera 3, 46012, Valencia, Spain
| | - Paula Oliete-Calvo
- Gene Expression and RNA Metabolism Laboratory, Centro de Investigación Príncipe Felipe (CIPF), C/E. Primo Yúfera 3, 46012, Valencia, Spain
| | - Encar García-Oliver
- Gene Expression and RNA Metabolism Laboratory, Centro de Investigación Príncipe Felipe (CIPF), C/E. Primo Yúfera 3, 46012, Valencia, Spain
| | - María de la Iglesia-Vayá
- Brain Connectivity Lab. Joint Unit FISABIO & Centro de Investigación Príncipe Felipe (CIPF), C/E. Primo Yúfera 3, 46012, Valencia, Spain
| | - Susana Rodríguez-Navarro
- Gene Expression and RNA Metabolism Laboratory, Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas (CSIC), C/Jaume Roig 11, 46010, Valencia, Spain. .,Gene Expression and RNA Metabolism Laboratory, Centro de Investigación Príncipe Felipe (CIPF), C/E. Primo Yúfera 3, 46012, Valencia, Spain.
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Li J, Cheng D, Zhu M, Yu H, Pan Z, Liu L, Geng Q, Pan H, Yan M, Yao M. OTUB2 stabilizes U2AF2 to promote the Warburg effect and tumorigenesis via the AKT/mTOR signaling pathway in non-small cell lung cancer. Am J Cancer Res 2019; 9:179-195. [PMID: 30662561 PMCID: PMC6332791 DOI: 10.7150/thno.29545] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 11/25/2018] [Indexed: 12/13/2022] Open
Abstract
Increasing evidence has confirmed that deubiquitinating enzymes play an important role in lung cancer progression. In the current study, we investigated the expression profile of deubiquitinating enzymes in non-small cell lung cancer (NSCLC) tissues and identified OTUB2 as an upregulated deubiquitinating enzyme. The role of OTUB2 in NSCLC is unknown. Methods: Quantitative, real-time PCR and Western blot were used to detect OTUB2 and U2AF2 expression in NSCLC tissues. The correlations between OTUB2 and U2AF2 expression and clinicopathologic features were then analyzed. We used In vitro Cell Counting Kit-8 (CCK-8) , colony formation , and trans-well invasion assays to investigate the function of OTUB2 and U2AF2 in tumorigenesis. The regulation of glycolysis by OTUB2 and U2AF2 was assessed by determining the extracellular acid ratio, glucose consumption, and lactate production. The mechanism of OTUB2 was explored through co-immunoprecipitation and mass spectrometry analyses. A xenograft model was also used to study the tumorigenesis role of OTUB2 In vivo. Results: OTUB2 expression was significantly upregulated in primary NSCLC tissues and greatly associated with metastasis, advanced tumor stages, poor survival, and recurrence. In NSCLC cell lines, OTUB2 promoted cell growth, colony formation, migration, and invasive activities. Mechanistic investigations showed that OTUB2 stimulated the Warburg effect and induced the activation of the serine/threonine kinase/mechanistic target of rapamycin kinase (AKT/mTOR) pathway in different NSCLC cells. More importantly, OTUB2 promoted NSCLC progression, which was largely dependent on the direct binding to and deubiquitination of U2AF2, at least in NSCLC cells. U2AF2 expression was also significantly upregulated in primary NSCLC tissues and dramatically associated with metastasis, advanced tumor stages, poor survival, and recurrence. Importantly, a positive correlation between the protein expression of OTUB2 and U2AF2 in NSCLC tissues was found. In vivo experiments indicated that OTUB2 promoted xenograft tumor growth of NSCLC cell. In addition, our results suggest that high expression of OTUB2, U2AF2 and PGK1 is significantly associated with worse prognosis in NSCLC patients. Conclusion: Taken together, the present study provides the first evidence that OTUB2 acts as a pivotal driver in NSCLC tumorigenesis by stabilizing U2AF2 and activating the AKT/mTOR pathway and the Warburg effect. It may serve as a new potential prognostic indicator and therapeutic target in NSCLC.
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Targeting CD26 suppresses proliferation of malignant mesothelioma cell via downmodulation of ubiquitin-specific protease 22. Biochem Biophys Res Commun 2018; 504:491-498. [PMID: 30197002 DOI: 10.1016/j.bbrc.2018.08.193] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 08/29/2018] [Indexed: 11/24/2022]
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive malignancy arising from mesothelial lining of pleura. It is associated with a poor prognosis, partly due to the lack of a precise understanding of the molecular mechanisms associated with its malignant behavior. In the present study, we expanded on our previous studies on cell cycle control of MPM cells by targeting CD26 molecule with humanized anti-CD26 monoclonal antibody (HuCD26mAb), focusing particularly on ubiquitin-specific protease 22 (USP22). We showed that USP22 protein expression is detected in clinical specimens of MPM and that USP22 knockdown, as well as CD26 knockdown, significantly inhibits the growth and proliferation of MPM cells in vitro and in vivo. Moreover, depletion of both USP22 and CD26 suppresses MPM cell proliferation even more profoundly. Furthermore, expression levels of USP22 correlate with those of CD26. HuCD26mAb treatment induces a decrease in USP22 level through its interaction with the CD26 molecule, leading to increased levels of ubiquitinated histone H2A and p21. By demonstrating a CD26-related linkage with USP22 in MPM cell inhibition induced by HuCD26mAb, our present study hence characterizes USP22 as a novel target molecule while concurrently suggesting a new therapeutic strategy for MPM.
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Gong Z, Liu J, Xie X, Xu X, Wu P, Li H, Wang Y, Li W, Xiong J. Identification of potential target genes of USP22 via ChIP-seq and RNA-seq analysis in HeLa cells. Genet Mol Biol 2018; 41:488-495. [PMID: 30088609 PMCID: PMC6082230 DOI: 10.1590/1678-4685-gmb-2017-0164] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 10/14/2016] [Indexed: 12/18/2022] Open
Abstract
The ubiquitin-specific protease 22 (USP22) is an oncogene and its expression is
upregulated in many types of cancer. In the nucleus, USP22 functions as one
subunit of the SAGA to regulate gene transcription. However, the genome-wide
USP22 binding sites and its direct target genes are yet clear. In this study, we
characterized the potential genomic binding sites of UPS22 and GCN5 by ChIP-seq
using specific antibodies in HeLa cells. There were 408 overlapping putative
target genes bound by both USP22 and GCN5. Motif analysis showed that the
sequences bound by USP22 and GCN5 shared two common motifs. Gene ontology (GO)
and pathway analysis indicated that the genes targeted by USP22 and GCN5 were
involved in different physiological processes and pathways. Further RNA-seq, GO
and pathway analyses revealed that knockdown of UPS22 induced differential
expression of many genes that participated in diverse physiological processes,
such as metabolic process. Integration of ChIP-seq and RNA-seq data revealed
that UPS22 bound to the promoters of 56 genes. These findings may provide new
insights into the regulation of USP22 on gene expression during the development
of cervical cancer.
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Affiliation(s)
- Zhen Gong
- College of Basic Medical Science, Jiujiang University, Jiujiang, Jiangxi, China
| | - Jianyun Liu
- Key Laboratory of Jiangxi Province for the Systemic Bio-medicine, Jiujiang University, Jiujiang, Jiangxi, China
| | - Xin Xie
- Key Laboratory of Jiangxi Province for the Systemic Bio-medicine, Jiujiang University, Jiujiang, Jiangxi, China
| | - Xiaoyuan Xu
- Key Laboratory of Jiangxi Province for the Systemic Bio-medicine, Jiujiang University, Jiujiang, Jiangxi, China
| | - Ping Wu
- Key Laboratory of Jiangxi Province for the Systemic Bio-medicine, Jiujiang University, Jiujiang, Jiangxi, China
| | - Huimin Li
- College of Basic Medical Science, Jiujiang University, Jiujiang, Jiangxi, China
| | - Yaqin Wang
- Reproductive Medical Center, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Weidong Li
- Key Laboratory of Jiangxi Province for the Systemic Bio-medicine, Jiujiang University, Jiujiang, Jiangxi, China
| | - Jianjun Xiong
- College of Basic Medical Science, Jiujiang University, Jiujiang, Jiangxi, China.,Key Laboratory of Jiangxi Province for the Systemic Bio-medicine, Jiujiang University, Jiujiang, Jiangxi, China
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Yang X, Zang H, Luo Y, Wu J, Fang Z, Zhu W, Li Y. High expression of USP22 predicts poor prognosis and advanced clinicopathological features in solid tumors: a meta-analysis. Onco Targets Ther 2018; 11:3035-3046. [PMID: 29872315 PMCID: PMC5973323 DOI: 10.2147/ott.s148662] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Introduction The expression of USP22 has been demonstrated to play a pivotal role in solid tumors. However, the prognostic value of USP22 still remains unknown. Materials and methods A systematic meta-analysis was performed to assess the prognostic value of USP22 in cancers. A literature collection was conducted from inception to June 8, 2017 by searching PubMed, Cochrane Library, Embase, Ovid and Web of Science databases. The pooled hazard ratio (HR) and odds ratio (OR) were used to correlate high expression of USP22 with overall survival (OS) and clinicopathological features. Results The results, pooled by 19 studies with 2,876 cases, indicated that high expression of USP22 predicted poor OS (HR=2.48, 95% CI: 2.11–2.84, p<0.001) and disease-free survival (DFS; HR=2.55, 95% CI: 2.05–3.05, p<0.001) of cancer patients. Furthermore, high expression of USP22 was also significantly associated with advanced clinicopathological parameters, including tumor stage, tumor differentiation, metastasis, nodal status and tumor size. Conclusion Our finding revealed that USP22 might be an indicator of poor prognosis and advanced clinicopathological features of solid tumors and could be served as a novel biomarker.
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Affiliation(s)
- Xiaohui Yang
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Haiyang Zang
- Department of Spleen and Stomach, Xinyi Municipal Hospital of Traditional Chinese Medicine, Xinyi, Jiangsu, China
| | - Yingbin Luo
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianchun Wu
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhihong Fang
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Weikang Zhu
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan Li
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Zhao HD, Tang HL, Liu NN, Zhao YL, Liu QQ, Zhu XS, Jia LT, Gao CF, Yang AG, Li JT. Targeting ubiquitin-specific protease 22 suppresses growth and metastasis of anaplastic thyroid carcinoma. Oncotarget 2018; 7:31191-203. [PMID: 27145278 PMCID: PMC5058749 DOI: 10.18632/oncotarget.9098] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 04/11/2016] [Indexed: 11/25/2022] Open
Abstract
Ubiquitin-specific protease 22 (USP22) aberrance has been implicated in several malignancies; however, whether USP22 plays a role in anaplastic thyroid carcinoma (ATC) remains unclear. Here, we report that USP22 expression is highly elevated in ATC tissues, which positively correlated with tumor size, extracapsular invasion, clinical stages, and poor prognosis of ATC patients. In vitro assays showed that USP22 depletion suppressed ATC cell survival and proliferation by decreasing Rb phosphorylation and cyclin D2, inactivating Akt, and simultaneously upregulating Rb; USP22 silencing restrained cell migration and invasion by inhibiting epithelial-mesenchymal transition; USP22 knockdown promoted mitochondrion- mediated and caspase-dependent apoptosis by upregulating Bax and Bid and promoting caspase-3 activation. Consistent with in vitro findings, downregulation of USP22 in ATC cells impeded tumor growth and lung metastasis in vivo. These results raise the applicability for USP22 as a useful predictor of ATC prognosis and a potential therapeutic target for ATC.
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Affiliation(s)
- Hua-Dong Zhao
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Hai-Li Tang
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Ning-Ning Liu
- Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China
| | - Ya-Li Zhao
- Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China
| | - Qin-Qin Liu
- Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China
| | - Xiao-Shan Zhu
- Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China
| | - Lin-Tao Jia
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Chun-Fang Gao
- Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China
| | - An-Gang Yang
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Jun-Tang Li
- Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China.,State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.,State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
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Ao N, Wang L, Liu Y. Prognostic and clinicopathological significance of ubiquitin-specific protease 22 overexpression in cancers: evidence from a meta-analysis. Onco Targets Ther 2017; 10:5533-5540. [PMID: 29200868 PMCID: PMC5702165 DOI: 10.2147/ott.s139458] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Purpose This meta-analysis study aimed to reveal the prognostic relevance of ubiquitin-specific protease 22 (USP22) expression in patients with cancers. Methods PubMed, Embase, and the Cochrane Library electronic databases were searched for relevant studies published up to April 2017. The prognostic value of USP22 expression was evaluated by hazard ratio with 95% confidence intervals (CIs). Relative risk (RR) with 95% CIs assessed the effects of USP22 expression on clinicopathological parameters. A total of 16 studies of 2,233 Chinese patients were included in the final meta-analysis. Results A significant association was found between USP22 overexpression and survival in patients with cancers. The pooled RR indicated that USP22 overexpression was related to histological grade, advanced tumor–node–metastasis stage, positive lymph node metastasis, and distant metastasis. Conclusion This meta-analysis demonstrated that USP22 could be a novel biomarker for predicting prognosis in patients with cancers in the Chinese population.
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Affiliation(s)
- Ning Ao
- Department of Pathology, Beijing Tiantan Hospital, Capital Medical University
| | - Liang Wang
- Department of Pathology, Chinese PLA General Hospital
| | - Yuqin Liu
- Department of Pathology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, Beijing, People's Republic of China
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Hong A, Lee JE, Chung KWANGCHUL. Ubiquitin-specific protease 22 (USP22) positively regulates RCAN1 protein levels through RCAN1 de-ubiquitination. J Cell Physiol 2015; 230:1651-60. [DOI: 10.1002/jcp.24917] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Accepted: 12/18/2014] [Indexed: 02/01/2023]
Affiliation(s)
- Ahyoung Hong
- Department of Systems Biology; College of Life Science and Biotechnology; Yonsei University; Seoul Republic of Korea
| | - Ji Eun Lee
- Department of Systems Biology; College of Life Science and Biotechnology; Yonsei University; Seoul Republic of Korea
| | - KWANG CHUL Chung
- Department of Systems Biology; College of Life Science and Biotechnology; Yonsei University; Seoul Republic of Korea
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Wang ZJ, Yang JL, Wang YP, Lou JY, Chen J, Liu C, Guo LD. Decreased histone H2B monoubiquitination in malignant gastric carcinoma. World J Gastroenterol 2013; 19:8099-8107. [PMID: 24307806 PMCID: PMC3848160 DOI: 10.3748/wjg.v19.i44.8099] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2013] [Revised: 09/23/2013] [Accepted: 10/22/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate H2B monoubiquitination (uH2B) and H3K4 di- and tri-methylation (H3K4-2me, H3K4-3me) levels and their clinical significance in gastric cancer (GC).
METHODS: Immunohistochemistry (IGC) was used to detect the differential levels of uH2B, H3K4-2me and H3K4-3me modifications in GC specimens from chemo/radiotherapy-naïve patients who underwent potentially curative surgical resection (n = 159) and in a random sampling of non-tumor gastric epithelium specimens (normal controls, n = 20). The immunohistochemistry (IHC)-detected modifications were classified as negative, low-level, or high-level using a dual-rated (staining intensity and percentage of positively-stained cells) semi-quantitative method. The relationships between uH2B modification levels and clinicopathological parameters of GC were assessed by a Wilcoxon rank sum test (pairwise comparisons) and the Kruskal-Wallis H test (multiple comparisons). The correlation between uH2B modification and survival was estimated by Kaplan-Meier analysis, and the role of uH2B as an independent prognostic factor for survival was assessed by multivariate Cox regression analysis.
RESULTS: The presence and level of H3K4-2me and H3K4-3me IHC staining was similar between the normal controls and GC specimens. In contrast, the level of uH2B was significantly lower in the malignant gastric tissues (vs normal control tissues) and decreased along with increases in dedifferentiation (well differentiated > moderately differentiated > poorly differentiated). The level of uH2B correlated with tumor differentiation (P < 0.001), Lauren’s diffuse- and intestinal-type classification (P < 0.001), lymph node metastasis (P = 0.049) and tumor-node-metastasis stage (P = 0.005). Patients with uH2B+ staining had higher 5-year survival rates than patients with uH2B-staining (52.692 ± 2.452 vs 23.739 ± 5.207, P < 0.001). The uH2B level was an independent prognostic factor for cancer-specific survival (95%CI: 0.237-0.677, P = 0.001).
CONCLUSION: uH2B displays differential IHC staining patterns corresponding to progressive stages of GC. uH2B may contribute to tumorigenesis and could be a potential therapeutic target.
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Ubiquitin-specific protease 22: a novel molecular biomarker in cervical cancer prognosis and therapeutics. Tumour Biol 2013; 35:929-34. [PMID: 23979981 DOI: 10.1007/s13277-013-1121-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 08/14/2013] [Indexed: 10/26/2022] Open
Abstract
Ubiquitin-specific protease 22 (USP22) exhibits an important function in tumor progression and oncogenesis. The aim of this study was to investigate the role of USP22 and the association with its potential targets in patients with cervical cancer. To our knowledge, this is the first study that determines the relationship between USP22 expression and clinicopathological significance in cervical cancer. The immunohistochemistry results showed that USP22 protein was overexpressed in cervical cancer samples compared with normal cervical tissues (P < 0.001). Moreover, clinicopathological analysis showed that USP22 expression was highly related to International Federation of Gynecology and Obstetrics stage, Ki67, lymph node metastasis, and histology grade. The results of Kaplan-Meier analysis indicated that patients with high USP22 expression had significantly shorter overall survival (OS) and disease-free survival (DFS) than patients with low expression of USP22 (P < 0.001). Multivariate Cox regression analysis revealed that USP22 expression status was an independent prognostic marker for both OS and DFS of patients with cervical cancer. It is suggested that USP22 overexpression may be associated with poor prognosis in cervical cancer. It may represent a novel prognostic biomarker or a target for improving the treatment efficiency of patients with cervical cancer.
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A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex. Mol Cell Biol 2013; 33:1487-502. [PMID: 23382074 DOI: 10.1128/mcb.00971-12] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Although 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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Piao S, Liu Y, Hu J, Guo F, Ma J, Sun Y, Zhang B. USP22 is useful as a novel molecular marker for predicting disease progression and patient prognosis of oral squamous cell carcinoma. PLoS One 2012; 7:e42540. [PMID: 22880026 PMCID: PMC3411815 DOI: 10.1371/journal.pone.0042540] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2012] [Accepted: 07/09/2012] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND AND OBJECTIVE The significance of ubiquitin-specific protease 22 (USP22) as a potential marker has been growing in the field of oncology. The aim of this study was to investigate the role of USP22 and the association with its potential targets in oral squamous cell carcinoma (OSCC). METHODS Immunohistochemistry was used to determine the expression of USP22 protein in 319 OSCC patients in comparison with 42 healthy controls. The clinical correlations and prognostic significance of the aberrantly expressed protein was evaluated to identify novel biomarker of OSCC. RESULTS The incidence of positive USP22 expression was 63.32% in 319 conventional OSCC tissues. The protein expression level of USP22 was concomitantly up-regulated from non-cancerous mucosa to primary carcinoma and from carcinomas to lymph node metastasis (P<0.001). Moreover, statistical analysis showed that positive USP22 expression was positively related to lymph node metastasis, Ki67, Cox-2 and recurrence. Furthermore, it was shown that patients with positive USP22 expression had significantly poorer outcome compared with patients with negative expression of USP22 for patients with positive lymph nodes. Multivariate Cox regression analysis revealed that USP22 expression level was an independent prognostic factor for both overall survival and disease-free survival (P<0.001 and P<0.001, respectively). Cancer cells with reduced USP22 expression exhibited reduced proliferation and colony formation evaluated by MTT and soft agar assays. CONCLUSION To our knowledge, this is the first study that determines the relationship between USP22 expression and prognosis in OSCC. We found that increased expression of USP22 is associated with poor prognosis in OSCC. USP22 may represent a novel and useful prognostic marker for OSCC.
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Affiliation(s)
- Songlin Piao
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Yanlong Liu
- Department of Colorectal Surgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Jing Hu
- Department of Breast Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Fulin Guo
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
- * E-mail: (FG); (BZ)
| | - Jie Ma
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Yao Sun
- Hard Tissue Lab, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Bin Zhang
- Hard Tissue Lab, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
- * E-mail: (FG); (BZ)
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Lin Z, Yang H, Kong Q, Li J, Lee SM, Gao B, Dong H, Wei J, Song J, Zhang DD, Fang D. USP22 antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required for mouse embryonic development. Mol Cell 2012; 46:484-94. [PMID: 22542455 DOI: 10.1016/j.molcel.2012.03.024] [Citation(s) in RCA: 247] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2011] [Revised: 01/17/2012] [Accepted: 03/22/2012] [Indexed: 02/07/2023]
Abstract
The NAD-dependent histone deacetylase Sirt1 antagonizes p53 transcriptional activity to regulate cell-cycle progression and apoptosis. We have identified a ubiquitin-specific peptidase, USP22, one of the 11 death-from-cancer signature genes that are critical in controlling cell growth and death, as a positive regulator of Sirt1. USP22 interacts with and stabilizes Sirt1 by removing polyubiquitin chains conjugated onto Sirt1. The USP22-mediated stabilization of Sirt1 leads to decreasing levels of p53 acetylation and suppression of p53-mediated functions. In contrast, depletion of endogenous USP22 by RNA interference destabilizes Sirt1, inhibits Sirt1-mediated deacetylation of p53 and elevates p53-dependent apoptosis. Genetic deletion of the usp22 gene results in Sirt1 instability, elevated p53 transcriptional activity and early embryonic lethality in mice. Our study elucidates a molecular mechanism in suppression of cell apoptosis by stabilizing Sirt1 in response to DNA damage and reveals a critical physiological function of USP22 in mouse embryonic development.
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Affiliation(s)
- Zhenghong Lin
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Spedale G, Timmers HTM, Pijnappel WWMP. ATAC-king the complexity of SAGA during evolution. Genes Dev 2012; 26:527-41. [PMID: 22426530 DOI: 10.1101/gad.184705.111] [Citation(s) in RCA: 139] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The yeast SAGA (Spt-Ada-Gcn5-acetyltransferase) coactivator complex exerts functions in gene expression, including activator interaction, histone acetylation, histone deubiquitination, mRNA export, chromatin recognition, and regulation of the basal transcription machinery. These diverse functions involve distinct modules within this multiprotein complex. It has now become clear that yeast SAGA has diverged during metazoan evolution into two related complexes, SAGA and ATAC, which exist in two flavors in vertebrates. The compositions of metazoan ATAC and SAGA complexes have been characterized, and functional analyses indicate that these complexes have important but distinct roles in transcription, histone modification, signaling pathways, and cell cycle regulation.
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Affiliation(s)
- Gianpiero Spedale
- Molecular Cancer Research, Netherlands Proteomics Center, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands
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Sela D, Chen L, Martin-Brown S, Washburn MP, Florens L, Conaway JW, Conaway RC. Endoplasmic reticulum stress-responsive transcription factor ATF6α directs recruitment of the Mediator of RNA polymerase II transcription and multiple histone acetyltransferase complexes. J Biol Chem 2012; 287:23035-45. [PMID: 22577136 DOI: 10.1074/jbc.m112.369504] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The basic leucine zipper transcription factor ATF6α functions as a master regulator of endoplasmic reticulum (ER) stress response genes. Previous studies have established that, in response to ER stress, ATF6α translocates to the nucleus and activates transcription of ER stress response genes upon binding sequence specifically to ER stress response enhancer elements in their promoters. In this study, we investigate the biochemical mechanism by which ATF6α activates transcription. By exploiting a combination of biochemical and multidimensional protein identification technology-based mass spectrometry approaches, we have obtained evidence that ATF6α functions at least in part by recruiting to the ER stress response enhancer elements of ER stress response genes a collection of RNA polymerase II coregulatory complexes, including the Mediator and multiple histone acetyltransferase complexes, among which are the Spt-Ada-Gcn5 acetyltransferase (SAGA) and Ada-Two-A-containing (ATAC) complexes. Our findings shed new light on the mechanism of action of ATF6α, and they outline a straightforward strategy for applying multidimensional protein identification technology mass spectrometry to determine which RNA polymerase II transcription factors and coregulators are recruited to promoters and other regulatory elements to control transcription.
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Affiliation(s)
- Dotan Sela
- Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA
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18
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USP22 acts as an oncogene by the activation of BMI-1-mediated INK4a/ARF pathway and Akt pathway. Cell Biochem Biophys 2012; 62:229-35. [PMID: 21928107 DOI: 10.1007/s12013-011-9287-0] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Recent studies provided strong support for the view that ubiquitin-specific protease 22 (USP22) plays a central role in cell-cycle progression and also in pathological processes such as oncogenesis. We have recently shown that USP22 levels are elevated in colorectal carcinoma with associated increase in the expression of several cell-cycle-related genes. However, the precise mechanism for these functions of USP22 at molecular level has not been fully elucidated. Currently, we investigated the role of USP22 in human colorectal cancer (CRC). We observed that USP22 expression was statistically significantly correlated positively with that of BMI-1, c-Myc and both, pAkt (Ser473), and pAkt (Thr308), in primary tumor tissues from 43 CRC patients. Down-regulation of USP22 expression in HCT116 colorectal cancer cells by siRNA resulted in the accumulation of cells in the G1 phase of the cell cycle. RNAi-knockdown of USP22 in HCT16 cells also led to the repression of BMI-1 and was accompanied by the up-regulation of p16INK4a and p14ARF, with a consequent decrease in E2F1 and p53 levels. In addition, down-regulation of c-Myc-targeted cyclin D2 was also noticed in cells treated with USP22-siRNA. Furthermore, our results showed that USP22 deletion also caused down-regulation of Akt/GSK3β activity, which can also contribute to the reduction of cyclin D2. Collectively, our current results suggest that USP22 may act as an oncogene in CRC as it positively regulates cell cycle via both BMI-1-mediated INK4a/ARF pathway and Akt signaling pathway.
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Yang DD, Cui BB, Sun LY, Zheng HQ, Huang Q, Tong JX, Zhang QF. The co-expression of USP22 and BMI-1 may promote cancer progression and predict therapy failure in gastric carcinoma. Cell Biochem Biophys 2012; 61:703-10. [PMID: 21735131 DOI: 10.1007/s12013-011-9229-x] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Recent experimental evidence support the model in which the simultaneous induction of BMI-1 and USP22 is critical during cancer progression. Whether this model may affect gastric cancer (GC) progression is worthy of additional study. In this study, we examined the significance of the USP22 and BMI-1 expression in GC (n = 219), non-cancerous mucosa (n = 37), and lymph node metastasis (n = 37). The protein expression level of USP22 and BMI-1 were concomitantly up-regulated from non-cancerous mucosa to primary carcinoma and from carcinomas to lymph node metastasis (P < 0.001). A statistical correlation was observed between USP22 and BMI-1 expression in GC tissues (n = 219, r = 0.634, P < 0.001) and in lymph node metastasis (n = 37, r = 0.689, P < 0.001). The incidence of positive expression was 57.08% for USP22, 49.32% for BMI-1, and 45.21% for USP22/BMI-1 in 219 GC tissues, respectively. Co-positive of USP22/BMI-1 was significantly correlated with gross features (x(2) = 14.256, P < 0.001), differentiation (x(2) = 5.872, P = 0.015), pT classification (x(2) = 18.486, P < 0.001), pN classification (x(2) = 9.604, P = 0.002), pM classification (x(2) = 32.766, P < 0.001), and AJCC stage (x(2) = 58.278, P < 0.001). Notably, high USP22/BMI-1 expression was significantly associated with shorter disease-specific survival (P < 0.001). By Cox regression analysis, co-positive of USP22/BMI-1 was found to be an independent prognostic factor (P = 0.002). Our results indicated the simultaneous activation of USP22 and BMI-1 may associate with GC progression and therapy failure.
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Affiliation(s)
- Dong-Dong Yang
- Department of Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Nangang District, Harbin 150001, Heilongjiang, People's Republic of China
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Xu H, Liu YL, Yang YM, Dong XS. Knock-down of ubiquitin-specific protease 22 by micro-RNA interference inhibits colorectal cancer growth. Int J Colorectal Dis 2012; 27:21-30. [PMID: 21773699 DOI: 10.1007/s00384-011-1275-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/28/2011] [Indexed: 02/04/2023]
Abstract
PURPOSE Increasing experimental evidences suggest that ubiquitin-specific protease 22 (USP22), a cancer stem cell marker, plays a crucial role in pathological processes of epithelial malignancies and other solid tumors, which makes it a potential target for cancer therapy. The aim of this study was to study the roles of USP22 in human colorectal cancer cell line HCT116 by suppressing USP22 expression with micro-interfering RNA (miRNA). METHODS With the knock-down of USP22, the changes of cellular proliferation, cell cycle, cell apoptosis, and major vault protein (MVP) expression were investigated. Furthermore, a tumor xenograft model in nude mice was injected with USP22 miRNA silencing vector and the immunohistochemical staining was performed to evaluate the USP22 expression in the tumor. RESULTS The knock-down of USP22 protein expression by miRNA resulted in the inhibition of cellular proliferation, the accumulation of cells in the G1 phase, the reduction of apoptosis, and the down-regulation of MVP expression. Furthermore, with orthotopic mice as a model, tumor growth was suppressed when USP22 miRNA silencing vector was injected. Immunohistochemical analyses of tumor sections revealed that USP22 expression in animals decreased when USP22 expression was inhibited by miRNA. CONCLUSION These results support the hypothesis that USP22 plays a crucial role in tumor formation and growth by regulating cell proliferation with USP22-dependent signaling pathway. Furthermore, USP22 acts as a major transcriptional factor to regulate MVP drug resistant gene. Taken together, targeting USP22 may offer additional possibilities in cancer therapy.
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Affiliation(s)
- Hui Xu
- Department of Oncosurgery, The Affiliated 4th Hospital of Harbin Medical University, 37 Yiyuan Street, Nangang District, Harbin, 150001, People's Republic of China
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Molina-Navarro MM, Martinez-Jimenez CP, Rodriguez-Navarro S. Transcriptional elongation and mRNA export are coregulated processes. GENETICS RESEARCH INTERNATIONAL 2011; 2011:652461. [PMID: 22567364 PMCID: PMC3335577 DOI: 10.4061/2011/652461] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2011] [Accepted: 08/10/2011] [Indexed: 01/06/2023]
Abstract
Chromatin structure complexity requires the interaction and coordinated work of a multiplicity of factors at different transcriptional regulation stages. Transcription control comprises a set of processes that ensures proper balance in the gene expression under different conditions, such as signals, metabolic states, or development. We could frame those steps from epigenetic marks to mRNA stability to support the holistic view of a fine-tune balance of final mRNA levels through mRNA transcription, export, stability, translation, and degradation. Transport of mRNA from the nucleus to the cytoplasm is a key process in regulated gene expression. Transcriptional elongation and mRNA export are coregulated steps that determine the mature mRNA levels in the cytoplasm. In this paper, recent insights into the coordination of these processes in eukaryotes will be summarised.
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22
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Deng MZ, Tao KX, Wang GB, Liu XH. SiRNA-mediated silencing of the USP22 gene inhibits cell proliferation in human gastric cancer cell line AGS. Shijie Huaren Xiaohua Zazhi 2011; 19:1985-1989. [DOI: 10.11569/wcjd.v19.i19.1985] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the impact of silencing of the USP22 gene by small interfering RNA (siRNA) on the proliferation of human gastric cancer AGS cells.
METHODS: Three USP22-specific siRNAs and a negative siRNA were designed and transfected into AGS cells using Lipofectamine 2000. Quantitative real-time PCR (qRT-PCR) and Western blot were utilized to detect the expression levels of USP22 mRNA and protein, respectively. Cell proliferation was measured using Cell Counting Kit-8 (CCK-8). The distribution of cell cycle was determined by flow cytometry.
RESULTS: All three USP22-specific siRNAs could silence the expression of the USP22 gene. Forty-eight hours after transfection, the expression levels of USP22 mRNA and protein were reduced by 80.47% ± 2.99% and 79.40% ± 3.58%, respectively; the reduced rate of cell proliferation was 27.33% ± 3.49%; and the proportion of gastric cancer cells arrested in G0/G1 phase increased significantly, while those arrested in S phase decreased significantly.
CONCLUSION: Transfection of USP22-specific siRNAs could effectively inhibit the expression of the USP22 gene and significantly suppress cell growth in human gastric cancer cell line AGS.
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Implication of USP22 in the regulation of BMI-1, c-Myc, p16INK4a, p14ARF, and cyclin D2 expression in primary colorectal carcinomas. ACTA ACUST UNITED AC 2011; 19:194-200. [PMID: 21052002 DOI: 10.1097/pdm.0b013e3181e202f2] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Increasing experimental evidence suggests that USP22 plays a crucial role in the pathologic processes of epithelial malignancies and other solid tumors. BMI-1, p16INK4a, p14ARF, cyclin D2, and c-Myc have been implicated in the regulation of the cell cycle mediated by USP22 in cell culture experiments. In this study, we examined whether these in vitro findings can be extrapolated to the in vivo situation. METHODS We measured the expression of USP22 and the candidate targets such as BMI-1, c-Myc, cyclin D2, p16INK4a, p14ARF by quantitative real time-polymerase chain reaction, Western blotting, and immunostaining in a series of 43 colorectal carcinomas (CRCs) and correlated the data with several clinicopathologic variables. RESULTS The frequency of overexpression (4-fold expression analysis) was 37.0% for USP22, 48.9% for BMI-1, 48.9% for c-Myc, and 58.0% for cyclinD2, respectively. Statistical correlation analysis at the mRNA level showed USP22 to be significantly correlated with BMI-1 (r=0.889, P<0.0001), c_Myc (r=0.573, P<0.0001), and cyclin D2 (r=0.872, P<0.0001), but not p16IN K4a (r=0.222, P=0.153) or p14Are (r=-0.154, P=0.325) by quantitative real time-polymerase chain reaction. These findings were confirmed by the Western blotting assay. Furthermore, the k-means cluster analysis showed that CRCs with high mRNA expression of USP22, BMI-1, c-Myc, and cyclin D2 were significantly correlated with the advanced AJCC stage (P=0.01) associated with poor prognosis. CONCLUSIONS The findings of this study supported dysregulation of a proposed functional pathway by upregulation of gene products in primary CRC.
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Liu YL, Yang YM, Xu H, Dong XS. Aberrant expression of USP22 is associated with liver metastasis and poor prognosis of colorectal cancer. J Surg Oncol 2010; 103:283-9. [PMID: 21337558 DOI: 10.1002/jso.21802] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2010] [Accepted: 10/22/2010] [Indexed: 11/07/2022]
Abstract
BACKGROUND The present study was aimed at clarifying the expression of ubiquitin carboxyl-terminal hydrolase 22 (USP22), a novel deubiquitinating enzyme gene, in colorectal cancer (CRC) and its clinical significance. METHODS USP22 expression was detected with quantitative RT-PCR, Western blot, and immunohistochemistry (IHC) in 43 CRCs and non-cancerous matched tissues. Furthermore, USP22 protein expression was analyzed in 192 CRC tumors by IHC to evaluate the association with survival. RESULTS In 43 paired fresh tissues, the expression level of USP22 was significantly higher in primary CRCs than that in the paired non-cancerous tissues at both mRNA and protein levels (P < 0.0001). Nuclear USP22 expression significantly increased from normal mucosa through adenoma to primary carcinoma (P < 0.0001) and from primary carcinoma to liver metastasis (P = 0.021). The incidence of positive USP22 expression was 54.16% in 192 conventional CRC tissues. Notably, high USP22 expression was significantly associated with shorter disease-specific survival (P < 0.0001) and shorter disease-free survival (P < 0.0001). Cox regression analysis showed USP22 was an independent prognostic parameter for CRC patients. CONCLUSION 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.
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Affiliation(s)
- Yan-Long Liu
- Department of Colorectal Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, PR China
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25
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Liu YL, Yang YM, Xu H, Dong XS. Increased expression of ubiquitin-specific protease 22 can promote cancer progression and predict therapy failure in human colorectal cancer. J Gastroenterol Hepatol 2010; 25:1800-5. [PMID: 21039844 DOI: 10.1111/j.1440-1746.2010.06352.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIMS Increasing experimental evidence suggests that ubiquitin-specific protease 22 (USP22) could exhibit a critical function in pathological processes, including oncogenesis and cell cycle progression. The aim of this study was to investigate the role of USP22 and the association with its potential targets in colorectal cancer (CRC). METHODS We evaluated the implication of USP22 and the candidate targets, such as B-cell-specific murine leukemia virus integration site-1 (BMI-1), cellular homolog of avian myelocytomatosis virus oncogene (c-Myc), cyclin D2, inhibitor of cyclin-dependent kinase (CDK) 4 (p16INK4a), and an alternate reading frame product of the CDKN2A locus (p14ARF), in matched samples comprising carcinoma and adjacent non-cancerous mucosa from 82 patients with CRC using quantitative reverse transcription-polymerase chain reaction and immunostaining analyses. RESULTS The USP22 mRNA expression in the CRC tissues was significantly higher than those in the non-cancerous mucosa tissues (P < 0.0001). Increased mRNA expression of USP22 was associated with advanced American Joint Committee on Cancer stage (P = 0.033) and high likelihood of therapy failure after radical resection (P < 0.0001). The Cox regression analysis revealed that the USP22 mRNA expression level was a significant factor for predicting prognosis (P < 0.0001). The statistical correlation analysis in mRNA levels showed that USP22 was strongly correlated with BMI-1 (r = 0.790, P < 0.0001), c-Myc (r = 0.528, P < 0.0001), and cyclin D2 (r = 0.657, P < 0.0001), but not p16INK4a (r = 0.103, P = 0.358) or p14ARF (r = -0.039, P = 0.731). CONCLUSION Our results indicate that activation of USP22 correlates with CRC progression and therapy failure. Additionally, the oncogenic role of USP22 in the progression of CRC can be mechanistically linked with BMI-1, c-Myc, and cyclin D2, but not with p16INK4a and p14ARF.
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Affiliation(s)
- Yan Long Liu
- Department of Colorectal Surgery, the Affiliated Tumor Hospital, Harbin Medical University, Harbin, China
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Mischerikow N, Spedale G, Altelaar AFM, Timmers HTM, Pijnappel WWMP, Heck AJR. In-depth profiling of post-translational modifications on the related transcription factor complexes TFIID and SAGA. J Proteome Res 2010; 8:5020-30. [PMID: 19731963 DOI: 10.1021/pr900449e] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The basal transcription factor TFIID and the chromatin-modifying complex SAGA, which have several subunits in common, are crucial for transcription regulation. Here, we describe an in-depth profiling of post-translational modifications (PTMs) on both TFIID and SAGA from yeast. We took a multipronged approach using high-resolution mass spectrometry (LC-MS) in combination with the proteases Trypsin, Chymotrypsin and Glu-C. The cumulative peptide identification data, at a false discovery rate <1%, allowed us to cover most TFIID and SAGA subunit sequences to near completion. Additionally, for TFIID/SAGA subunits, we identified 118/102 unique phosphorylated and 54/61 unique lysine acetylated sites. Especially, several lysine residues on the SAGA subunits Spt7p and Sgf73p were found to be acetylated. Using a spectral counting approach, we found that the shared subunit TAF5p is phosphorylated to a significant greater extent in SAGA than in TFIID. Finally, we were able to map for the first time the cleavage site in Spt7p that is related to formation of the SAGA-like complex SLIK/SALSA. In general, our combination of tandem affinity enrichment, digestion with different proteases, extensive prefractionation and high-resolution LC-MS identifies a large number of PTMs of TFIID and SAGA/SLIK that might aid in future functional studies on these transcription factors.
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Affiliation(s)
- Nikolai Mischerikow
- Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Centre for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
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27
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Sowa ME, Bennett EJ, Gygi SP, Harper JW. Defining the human deubiquitinating enzyme interaction landscape. Cell 2009; 138:389-403. [PMID: 19615732 PMCID: PMC2716422 DOI: 10.1016/j.cell.2009.04.042] [Citation(s) in RCA: 1254] [Impact Index Per Article: 78.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2008] [Revised: 02/09/2009] [Accepted: 04/20/2009] [Indexed: 01/11/2023]
Abstract
Deubiquitinating enzymes (Dubs) function to remove covalently attached ubiquitin from proteins, thereby controlling substrate activity and/or abundance. For most Dubs, their functions, targets, and regulation are poorly understood. To systematically investigate Dub function, we initiated a global proteomic analysis of Dubs and their associated protein complexes. This was accomplished through the development of a software platform called CompPASS, which uses unbiased metrics to assign confidence measurements to interactions from parallel nonreciprocal proteomic data sets. We identified 774 candidate interacting proteins associated with 75 Dubs. Using Gene Ontology, interactome topology classification, subcellular localization, and functional studies, we link Dubs to diverse processes, including protein turnover, transcription, RNA processing, DNA damage, and endoplasmic reticulum-associated degradation. This work provides the first glimpse into the Dub interaction landscape, places previously unstudied Dubs within putative biological pathways, and identifies previously unknown interactions and protein complexes involved in this increasingly important arm of the ubiquitin-proteasome pathway.
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Affiliation(s)
- Mathew E. Sowa
- Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
| | - Eric J. Bennett
- Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
| | - Steven P. Gygi
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
| | - J. Wade Harper
- Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
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28
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Reyes-Turcu FE, Ventii KH, Wilkinson KD. Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem 2009; 78:363-97. [PMID: 19489724 DOI: 10.1146/annurev.biochem.78.082307.091526] [Citation(s) in RCA: 1118] [Impact Index Per Article: 69.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Deubiquitinating enzymes (DUBs) are proteases that process ubiquitin or ubiquitin-like gene products, reverse the modification of proteins by a single ubiquitin(-like) protein, and remodel polyubiquitin(-like) chains on target proteins. The human genome encodes nearly 100 DUBs with specificity for ubiquitin in five gene families. Most DUB activity is cryptic, and conformational rearrangements often occur during the binding of ubiquitin and/or scaffold proteins. DUBs with specificity for ubiquitin contain insertions and extensions modulating DUB substrate specificity, protein-protein interactions, and cellular localization. Binding partners and multiprotein complexes with which DUBs associate modulate DUB activity and substrate specificity. Quantitative studies of activity and protein-protein interactions, together with genetic studies and the advent of RNAi, have led to new insights into the function of yeast and human DUBs. This review discusses ubiquitin-specific DUBs, some of the generalizations emerging from recent studies of the regulation of DUB activity, and their roles in various cellular processes.
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Affiliation(s)
- Francisca E Reyes-Turcu
- Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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29
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Rodríguez-Navarro S. Insights into SAGA function during gene expression. EMBO Rep 2009; 10:843-50. [PMID: 19609321 DOI: 10.1038/embor.2009.168] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2009] [Accepted: 06/17/2009] [Indexed: 12/26/2022] Open
Abstract
Histone modifications are a crucial source of epigenetic control. SAGA (Spt-Ada-Gcn5 acetyltransferase) is a chromatin-modifying complex that contains two distinct enzymatic activities, Gcn5 and Ubp8, through which it acetylates and deubiquitinates histone residues, respectively, thereby enforcing a pattern of modifications that is decisive in regulating gene expression. Here, I discuss the latest contributions to understanding the roles of the SAGA complex, highlighting the characterization of the SAGA-deubiquitination module, and emphasizing the functions newly ascribed to SAGA during transcription elongation and messenger-RNA export. These findings suggest that a crosstalk exists between chromatin remodelling, transcription and messenger-RNA export, which could constitute a checkpoint for accurate gene expression. I focus particularly on the new components of human SAGA, which was recently discovered and confirms the conservation of the SAGA complex throughout evolution.
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30
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Cler E, Papai G, Schultz P, Davidson I. Recent advances in understanding the structure and function of general transcription factor TFIID. Cell Mol Life Sci 2009; 66:2123-34. [PMID: 19308322 PMCID: PMC11115924 DOI: 10.1007/s00018-009-0009-3] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2009] [Revised: 02/19/2009] [Accepted: 02/23/2009] [Indexed: 01/18/2023]
Abstract
The general transcription factor TFIID is a macromolecular complex comprising the TATA-binding protein (TBP) and a set of 13-14 TBP associated factors (TAFs). This review discusses biochemical, genetic and electron microscopic data acquired over the past years that provide a model for the composition, organisation and assembly of TFIID. We also revisit ideas on how TFIID is recruited to the promoters of active and possibly repressed genes. Recent observations show that recognition of acetylated and methylated histone residues by structural domains in several TAFs plays an important role. Finally, we highlight several genetic studies suggesting that TFIID is required for initiation of transcription, but not for maintaining transcription once a promoter is in an active state.
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Affiliation(s)
- Emilie Cler
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, 67404 Illkirch Cedex, France
| | - Gabor Papai
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, 67404 Illkirch Cedex, France
| | - Patrick Schultz
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, 67404 Illkirch Cedex, France
| | - Irwin Davidson
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, 67404 Illkirch Cedex, France
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The human SPT20-containing SAGA complex plays a direct role in the regulation of endoplasmic reticulum stress-induced genes. Mol Cell Biol 2008; 29:1649-60. [PMID: 19114550 DOI: 10.1128/mcb.01076-08] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
One of the central questions in eukaryotic transcription is how activators can transmit their signal to stimulate gene expression in the context of chromatin. The multisubunit SAGA coactivator complex has both histone acetyltransferase and deubiquitination activities and remodels chromatin to allow transcription. Whether and how SAGA is able to regulate transcription at specific loci is poorly understood. Using mass spectrometry, immunoprecipitation, and Western blot analysis, we have identified human SPT20 (hSPT20) as the human homologue of the yeast Spt20 and show that hSPT20 is a bona fide subunit of the human SAGA (hSAGA; previously called TFTC/STAGA/PCAF) complex and that hSPT20 is required for the integrity of the hSAGA complex. We demonstrate that hSPT20 and other hSAGA subunits, together with RNA polymerase II, are specifically recruited to genes induced by endoplasmic reticulum (ER) stress. In good agreement with the recruitment of hSAGA to the ER stress-regulated genes, knockdown of hSTP20 hampers ER stress response. Surprisingly, hSPT20 recruitment was not observed for genes induced by another type of stress. These results provide evidence for a direct and specific role of the hSPT20-containing SAGA complex in transcriptional induction of ER stress-responsive genes. Thus, hSAGA regulates the transcription of stress-responsive genes in a stress type-dependent manner.
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