腫瘤的發(fā)生被認(rèn)為是處于活躍狀態(tài)的正常細(xì)胞在基因錯(cuò)誤調(diào)控后所產(chǎn)生的不可逆后果。同時(shí)該過程賦予了癌細(xì)胞重新分化的能力。新的證據(jù)表明,實(shí)體腫瘤細(xì)胞具有向神經(jīng)細(xì)胞轉(zhuǎn)化的能力。但目前,其機(jī)制尚不清楚。組蛋白和DNA修飾酶對染色質(zhì)的動態(tài)調(diào)節(jié)是多種細(xì)胞命運(yùn)特化的關(guān)鍵因素。大量的研究表明,諸多的表觀遺傳學(xué)因子參與到了腫瘤的發(fā)生發(fā)展當(dāng)中來并在神經(jīng)的發(fā)育過程中起著非常重要的作用,這其中就包括Enhancer of zeste homolog 2（EZH2）、DNA methyltransferase 1（DNMT1）、Histone deacetylase 1（HDAC1）、Lysine（K）-specificdemethylase 1A（LSD1）這四個(gè)表觀遺傳學(xué)蛋白因子。研究表明,包括H3K4me1/2/3、H3K27me1/2/3、H3K9ac等在內(nèi)的組蛋白修飾和DNA甲基化的大量出現(xiàn)在維持神經(jīng)干細(xì)胞干性方面起著重要作用。這類表觀修飾的下降是促進(jìn)神經(jīng)干細(xì)胞向終端分化的重要因素。EZH2作為Polycomb repressive complex 2（PRC2）的酶活亞基,是催化H3K27me3形成、維... 

【文章來源】：南京大學(xué)江蘇省 211工程院校 985工程院校 教育部直屬院校

【文章頁數(shù)】：131 頁

【學(xué)位級別】：博士

【文章目錄】：
Abstract
中文摘要
Abbreviations
Chapter Ⅰ: Review: Epigenetics modification factors and signal pathways involve intumorigenesis and neurodevelopment
    1. Tumorigenesis and development
    2. Epithelial-to-mesenchymal transition（EMT）
    3. Neurodevelopment
    4. Cross-talk between tumors and nerves
    5. Epigenetics modification
        5.1 DNA methylation
        5.2 Histone modifications and corresponding enzymes
            5.2.1 Dynamic switch between methylation and demethylation in lysines ofhistones
            5.2.2 Dynamic switch between acetylation and deacetylation in lysines ofhistones
        5.3 Modifications in non-histone proteins
        5.4 Relationship between epigenetics modifications and tumorigenesis
        5.5 Relationship between epigenetics modifications and neurodevelopment
    6. Signal pathways make critical role in tumorigenesis and neurodevelopment
        6.1 Wnt/β-catenin pathway and its role in tumorigenesis and neurodevelopment
        6.2 TGF-β pathway and its role in tumorigenesis and neurodevelopment
    7. Summary
    8. Reference
Chapter Ⅱ: Study on the differentiation of tumor cells into neuron-like cells and itsunderlying mechanism
    1. Introduction
    2. Materials and methods
    3. Results and conclusion
        3.1 Synergistic targeting at multiple of epigenetics modification enzymes can effectively inhibit tumor progression and promote neural-differentiation of tumors
            3.1.1 Knockdown of chromatin modification enzymes inhibits tximor progression
            3.1.2 Knockdown of chromatin modification enzymes induces neuron-like differentiation in cancer cell lines
            3.1.3 Interactions between epigenetic modification enzymes and between the enzymes and the key signal transducers of TGF-β and Wnt pathway
            3.1.4 Combined targeting at chromatin modification enzymes efficiently inhibit tumor progression and induces neuron-like differentiation of cancer cell line
            3.1.5 Binding of epigenetic modification enzymes to promoters and chromatin modifications in the promoters are changed in cells treated with TALE
            3.1.6 TALE treatment leads to neuronal differentiation in neural progenitor/stem cells
            3.1.7 Conclusion
        3.2 Knockdown of EZH2 leads to neuron-like differentiation in SW480 cells and reduce of malignancy
            3.2.1 Knockdown of EZH2, but not other epigenetic modification factors, leads to neuron-like differentiation in SW480 cells
            3.2.2 Knockdown of EZH2 downregulates protein expression of HDAC1, LSD1,DNMT1, and of P-CAT and SMAD transducers though Ub-dependent degradation way
            3.2.3 Reduced EZH2 expression enhances ubiquitination of its interaction partners
            3.2.4 EZH2 knockdown accelerates protein degradation and inhibits Wnt and TGF-psignaling transduction
            3.2.5 EZH2 promotes expression of its interaction partners
            3.2.6 EZH2 mediates maintaining stability of its interaction partners by coordinating with USP7
            3.2.7 EZH2 plays central role in binding of epigenetic modification enzymes to target gene promoters
            3.2.8 Conclusion
    4. Discussion
    5. Reference
Appendix
Publications
Acknowledgement



本文編號：3002004