期刊
NUCLEIC ACIDS RESEARCH
卷 49, 期 8, 页码 4421-4440出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab209
关键词
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资金
- National Natural Science Foundation of China [31871279, 82073122, 81702794]
- Beijing Municipal Education Commission [CITTCD201804088]
This study reveals the regulation of EZH2 abundance and function by USP7 in cancer cells, highlighting the potential of USP7 as a therapeutic target for cancer intervention. The physical association between USP7 and PRC2 complex plays a critical role in cell growth, proliferation, and tumorigenesis, with implications for histological grades and prognosis of tumor patients.
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.
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