组蛋白H2A去泛素化酶MYSM1在结肠癌发生发展过程中的作用及其机制研究

项目名称： 组蛋白H2A去泛素化酶MYSM1在结肠癌发生发展过程中的作用及其机制研究

项目编号： No.81472633

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王涛

作者单位： 中国人民解放军第四军医大学

项目金额： 75万元

中文摘要： 组蛋白泛素化是表观遗传修饰的重要形式之一，参与调控基因转录、细胞周期和DNA损伤修复等事件。MYSM1是组蛋白H2A特异性去泛素化酶，文献和我们前期工作证实MYSM1对造血干细胞和多种免疫细胞的发育及功能十分重要。虽然组蛋白泛素化修饰与肿瘤关系密切，但MYSM1在肿瘤中的作用尚无报道。我们近期发现MYSM1在结肠粘膜上皮细胞胞核中高表达，但在肿瘤中其表达则随肿瘤恶行程度升高而降低。此外，MYSM1缺失能引起基因组稳定性下降、p16降低和S期细胞增多及细胞增殖异常。上述研究提示MYSM1可能在肿瘤发生中扮演重要角色。为探明MYSM1对肿瘤的作用及其机制，本课题拟验证MYSM1与结肠癌的相关性，明确其在结肠癌发生中的作用，寻找MYSM1的共作用分子并确定其靶基因，探索MYSM1调控基因转录的分子机制。本课题试图阐明MYSM1在结肠癌中的作用及机制，将为系统认识肿瘤表观遗传网络提供新线索。

中文关键词： C08_结；直肠肿瘤；组蛋白去泛素化酶；Mysm1；肿瘤发生；转录调控

英文摘要： Histone ubiquitination is one of the important epigenetic histone modifications and plays vital roles in gene regulation, cell cycle and DNA damage-repair. MYSM1 is a specific H2A deubiquitinase. We and others have proved that MSYM1 is important for hematopoietic stem cell and immune cells development and function. Although histone ubiquitination is closely related with cancer, the functions of MYSM1 in cancer remains unclear. We recently found that MYSM1 is highly expressed in normal nuclei of colon mucosa epithelial cells but is down-regulated in colon cancer, especially in undifferentiated colon cancer. Further studies revealed that MYSM1 deficiency caused instability of the chromatin, down-regulated p16, more cells in S phage and abnormal cell proliferation. These results indicated MYSM1 plays important role in tumorgenesis. We plan to verify the correlation between MYSM1 and colon cancer, explore its role in colon cancer tumorgenesis, find out the partner of MYSM1 complex and its downstream target gene. We will also research on the molecular mechanisms of how MSYM1 regulates target gene transcription in this project. We hope to clarify the role and mechanisms of MYSM1 in colon cancer, providing new clues for systemic understanding of epigenetic net in tumorgenesis.

英文关键词： colon cancer;Histone deubiquitinase;Mysm1;tumorgenesis;transcriptional regulation