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Bimodal regulation of the PRC2 complex by USP7 underlies tumorigenesis.

ABSTRACT: 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.

SUBMITTER: Su D

PROVIDER: S-EPMC8096222 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Bimodal regulation of the PRC2 complex by USP7 underlies tumorigenesis.

Su Dongxue D Wang Wenjuan W Hou Yongqiang Y Wang Liyong L Yi Xianfu X Cao Cheng C Wang Yuejiao Y Gao Huan H Wang Yue Y Yang Chao C Liu Beibei B Chen Xing X Wu Xiaodi X Wu Jiajing J Yan Dong D Wei Shuqi S Han Lulu L Liu Shumeng S Wang Qian Q Shi Lei L Shan Lin L

Nucleic acids research 20210501 8

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 loadin ...[more]

PMID: 33849069

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Project description:Rationale: MCL-1 is up-regulated in cancer and a target for cancer treatment. How MCL-1 is up-regulated and whether MCL-1 up-regulation plays a role in tumorigenic process is not well-known. Arsenic and benzo(a)pyrene (BaP) are well-recognized lung carcinogens and we recently reported that arsenic and BaP co-exposure acts synergistically in inducing cancer stem cell (CSC)-like property and lung tumorigenesis. This study was performed to further investigate the underlying mechanism focusing on the role of MCL-1. Methods: The spheroid formation assay and nude mouse tumorigenesis assay were used to determine the CSC-like property and tumorigenicity of arsenic plus BaP co-exposure-transformed human bronchial epithelial BEAS-2B cells, respectively. Biochemical, pharmacological and genetic approaches were used to manipulate gene expressions, dissect signaling pathways and determine protein-protein interactions. Both loss-of-function and gain-of-function approaches were used to validate the role of MCL-1 in arsenic plus BaP co-exposure-enhanced CSC-like property and tumorigenicity. Results: Arsenic plus BaP co-exposure-transformed cells express significantly higher protein levels of MCL-1 than the passage-matched control, arsenic or BaP exposure alone-transformed cells. Knocking down MCL-1 levels in arsenic plus BaP co-exposure-transformed cells significantly reduced their apoptosis resistance, CSC-like property and tumorigenicity in mice. Mechanistic studies revealed that arsenic plus BaP co-exposure up-regulates MCL-1 protein levels by synergistically activating the PI3K/Akt/mTOR pathway to increase the level of a deubiquitinase USP7, which in turn reduces the level of MCL-1 protein ubiquitination and prevents its subsequent proteasome degradation. Conclusions: The deubiquitinase USP7-mediated MCL-1 up-regulation enhances arsenic and BaP co-exposure-induced CSC-like property and tumorigenesis, providing the first evidence demonstrating that USP7 stabilizes MCL-1 protein during the tumorigenic process.

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Bimodal regulation of the PRC2 complex by USP7 underlies tumorigenesis.

Publications

Bimodal regulation of the PRC2 complex by USP7 underlies tumorigenesis.

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