去泛素化酶USP7协同EZH2促进肿瘤发生发展的表观遗传调控机制的研究

EZH2是肿瘤发生发展的关键驱动蛋白，在多种肿瘤组织中呈高表达，但相关因子如何调控EZH2表达及功能的表观遗传机制还尚待阐明。此外，EZH2小分子抑制剂已经进入临床肿瘤治疗的试验阶段，但大部分实体肿瘤对其并不敏感，且由于EZH2在肿瘤中异常高表达、发生二次突变及使用抑制剂后部分EZH2保留酶活性均易引发耐药现象。我们初步研究表明，EZH2可以和去泛素化酶USP7相互作用，USP7可通过其蛋白去泛素化酶活性稳定EZH2蛋白水平。在转录调控过程中，USP7行使H2BK120去泛素化酶功能是EZH2发挥甲基转移酶功能的前提。本项目拟探讨USP7通过蛋白翻译后修饰及转录调控两条表观遗传调控途径协同EZH2发挥作用促进肿瘤发生发展的分子机制，并构建相关耐药细胞系，试分析USP7是否可以成为代替EZH2的新靶点。本研究的开展将有助于我们进一步认识肿瘤发生发展的机制，并为肿瘤的防治提供新思路和新靶点。

EZH2, is a classical etiology factor in the initiation and progression of carciogenesis. As the histone H3K27 methyltransferase, the level of the expression of EZH2 strongly correlates with histological grades and prognosis of tumor patients, while its upstream regulation mechanism remains to be explored. In addition, most of the EZH2 small molecule inhibitors have been used in the experimental stage of clinical tumor treatment, while most solid tumors are not sensitive to them. Meanwhile, the abnormal high expression, secondary mutation of EZH2 in tumors and the retained methlytransferase activity of EZH2 after using inhibitors lead to drug resistance Recently, we showed that EZH2 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 H2BK120 deuibiquitination is a prerequisite for chromatin loading of PRC2 thus H3K27 trimethylation. In this study, we propose to employ multiple genome-wide approaches to systematically investigate the dual role for USP7 in the regulation of the abundance and function of EZH2 in tumorigenesis and construct related resistant cell lines to analyze whether USP7 can be a new target to replace EZH2. We envision that the furtherance in understanding of the molecular mechanisms governing modification and regulation of the key factors in tumor will improve anti-cancer drug design and benefit the therapeutic pursuits for the disease.