Bimodal regulation of the PRC2 complex by USP7 underlies tumorigenesis.
Bimodal regulation of the PRC2 complex by USP7 underlies tumorigenesis.
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USP7 对 PRC2 复合物的双模式调节是肿瘤发生的基础
DOI：
10.1093/nar/gkab209
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发表时间：
2021-05-07
影响因子：
14.9
通讯作者：
Shan L
中科院分区：
文献类型：
--
作者：
Su D;Wang W;Hou Y;Wang L;Yi X;Cao C;Wang Y;Gao H;Wang Y;Yang C;Liu B;Chen X;Wu X;Wu J;Yan D;Wei S;Han L;Liu S;Wang Q;Shi L;Shan L
虽然EZH 2（polycomb repressive complex 2，PRC 2）的催化亚基）的过表达是多种癌症的显著特征，但其丰度和功能的调控仍不清楚。我们在这里报告，PRC 2复合物与癌细胞中的泛素特异性蛋白酶USP 7物理相关，其中USP 7起去泛素化和稳定EZH 2的作用。有趣的是，我们发现USP 7催化的H2 BK 120 ub 1去泛素化是PRC 2染色质负载的先决条件，因此H3 K27三甲基化，并且该过程不受PRC 1催化的H2 AK 119泛素化的影响。对USP 7/PRC 2复合物转录靶点的全基因组分析鉴定了一组基因，包括参与细胞生长和增殖的FOXO 1。我们证明了USP 7/PRC 2复合物在体外和体内驱动癌细胞增殖和肿瘤发生。我们发现，在肿瘤进展过程中，USP 7和EZH 2的表达均升高，对应于FOXO 1表达的降低，并且USP 7和EZH 2的表达水平与肿瘤患者的组织学分级和预后密切相关。这些结果揭示了USP 7在调节EZH 2的丰度和功能中的双重作用，支持了将USP 7作为癌症干预的治疗靶点的追求。
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.
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DOI：
10.1097/igc.0b013e318296a265
发表时间：
2013-07
期刊：
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society
影响因子：
--
作者：
Eskander RN;Ji T;Huynh B;Wardeh R;Randall LM;Hoang B
通讯作者：
Hoang B
DOI：
10.1073/pnas.1703966114
发表时间：
2017-11-14
影响因子：
11.1
作者：
Januario, Thomas;Ye, Xiaofen;Yauch, Robert L.
通讯作者：
Yauch, Robert L.
DOI：
10.1016/j.bbrc.2010.08.082
发表时间：
2010-09-24
影响因子：
3.1
作者：
de Bie, Prim;Zaaroor-Regev, Daphna;Ciechanover, Aaron
通讯作者：
Ciechanover, Aaron
影响因子：
16.6
作者：
通讯作者：
--
影响因子：
4.6
作者：
Georges, Anna;Coyaud, Etienne;Frappier, Lori
通讯作者：
Frappier, Lori