Bimodal regulation of the PRC2 complex by USP7 underlies tumorigenesis
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research..
Although overexpression of EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is an eminent feature of various cancers, the regulation of its abundance and function remains insufficiently understood. We report here that the PRC2 complex is physically associated with ubiquitin-specific protease USP7 in cancer cells where USP7 acts to deubiquitinate and stabilize EZH2. Interestingly, we found that USP7-catalyzed H2BK120ub1 deubiquitination is a prerequisite for chromatin loading of PRC2 thus H3K27 trimethylation, and this process is not affected by H2AK119 ubiquitination catalyzed by PRC1. Genome-wide analysis of the transcriptional targets of the USP7/PRC2 complex identified a cohort of genes including FOXO1 that are involved in cell growth and proliferation. We demonstrated that the USP7/PRC2 complex drives cancer cell proliferation and tumorigenesis in vitro and in vivo. We showed that the expression of both USP7 and EZH2 elevates during tumor progression, corresponding to a diminished FOXO1 expression, and the level of the expression of USP7 and EZH2 strongly correlates with histological grades and prognosis of tumor patients. These results reveal a dual role for USP7 in the regulation of the abundance and function of EZH2, supporting the pursuit of USP7 as a therapeutic target for cancer intervention.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:49 |
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| Enthalten in: |
Nucleic acids research - 49(2021), 8 vom: 07. Mai, Seite 4421-4440 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Su, Dongxue [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 28.05.2021 Date Revised 28.05.2021 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/nar/gkab209 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Bimodal regulation of the PRC2 complex by USP7 underlies tumorigenesis |
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| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. | ||
| 520 | |a Although overexpression of EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is an eminent feature of various cancers, the regulation of its abundance and function remains insufficiently understood. We report here that the PRC2 complex is physically associated with ubiquitin-specific protease USP7 in cancer cells where USP7 acts to deubiquitinate and stabilize EZH2. Interestingly, we found that USP7-catalyzed H2BK120ub1 deubiquitination is a prerequisite for chromatin loading of PRC2 thus H3K27 trimethylation, and this process is not affected by H2AK119 ubiquitination catalyzed by PRC1. Genome-wide analysis of the transcriptional targets of the USP7/PRC2 complex identified a cohort of genes including FOXO1 that are involved in cell growth and proliferation. We demonstrated that the USP7/PRC2 complex drives cancer cell proliferation and tumorigenesis in vitro and in vivo. We showed that the expression of both USP7 and EZH2 elevates during tumor progression, corresponding to a diminished FOXO1 expression, and the level of the expression of USP7 and EZH2 strongly correlates with histological grades and prognosis of tumor patients. These results reveal a dual role for USP7 in the regulation of the abundance and function of EZH2, supporting the pursuit of USP7 as a therapeutic target for cancer intervention | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Wang, Wenjuan |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Yongqiang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Liyong |e verfasserin |4 aut | |
| 700 | 1 | |a Yi, Xianfu |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yuejiao |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Huan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yue |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Beibei |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xing |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Xiaodi |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Jiajing |e verfasserin |4 aut | |
| 700 | 1 | |a Yan, Dong |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Shuqi |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Lulu |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Shumeng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Shan, Lin |e verfasserin |4 aut | |
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