组蛋白乙酰化增强转录因子Sp1诱导的mda-7基因转录激活

发布时间：2018-05-06 15:32

本文选题：HDAC4 + HDAC抑制剂　；参考：《东北师范大学》2011年硕士论文

【摘要】：Mda-7/IL-24 (黑色素瘤分化相关基因/白介素-24)最早发现是作为一种细胞因子,在人外周血单核细胞(PBMC)中能够被PHA或LPS诱导表达。Mda-7基因定位于IL - 10相关基因的基因簇中,是一个Th1细胞促进因子。腺病毒介导的mda-7促进IL - 6和IFN -γ的表达,并诱导黑色素瘤细胞分泌干扰素-γ和IL - 6。除此之外,mda-7也是一种肿瘤抑制基因,在正常黑素细胞中组成性表达,以维持细胞的正常生理功能,并诱导细胞终末分化。但随着黑色素瘤的进程,其表达逐渐减少,在转移阶段基本检测不到。腺病毒介导的mda-7异位表达可以选择性地诱导肿瘤细胞大范围的凋亡而对正常细胞的的副作用很小。此外,有证据表明,肿瘤细胞中缺少mda-7的表达不是基因突变的结果,对比癌症和正常细胞没有发现基因结构改变。癌细胞中mda-7能够被诱导表达的事实表明可能有其他机制调控mda-7的表达。据推测,如组蛋白乙酰化修饰的表观遗传变化可能在mda-7的表达调控中发挥作用,但是还没有相关研究的报道。在本研究中,我们证明组蛋白去乙酰酶抑制剂TSA和NaBu能够激活mda-7的表达,组蛋白去乙酰化酶4(HDAC4)能够部分逆转这一作用。同时也发现HDAC4过表达后mda-7启动子处的组蛋白乙酰化水平降低并且抑制了转录因子Sp1与mda-7启动子的结合。另外,组蛋白去乙酰化酶抑制剂TSA诱导组蛋白超乙酰化,促进Sp1与mda-7启动子结合,进而激活mda-7的表达。因此,我们得出结论组蛋白乙酰化修饰在调控mda-7表达中发挥重要作用,并且转录因子Sp1参与此过程。
[Abstract]:Mda-7/IL-24 (melanoma differentiation related gene / interleukin-24) was first found as a cytokine in human peripheral blood mononuclear cells (PBMC), which can be induced by PHA or LPS to express .Mda-7 gene in the gene cluster of IL-10 related gene. It is a Th1 cell promoting factor. Adenovirus-mediated mda-7 enhanced the expression of IL-6 and IFN-纬, and induced the secretion of interferon- 纬 and IL-6 by melanoma cells. In addition, mda-7 is also a tumor suppressor gene, which is constitutively expressed in normal melanocytes to maintain normal physiological function and induce terminal differentiation. However, with the progression of melanoma, the expression of melanoma decreased gradually and was not detected in metastatic stage. Adenovirus-mediated heterotopic expression of mda-7 can selectively induce a wide range of apoptosis in tumor cells with little side effect on normal cells. In addition, there is evidence that the lack of mda-7 expression in tumor cells is not the result of gene mutation, and no structural changes were found in cancer and normal cells. The fact that mda-7 can be induced in cancer cells suggests that there may be other mechanisms to regulate the expression of mda-7. It is speculated that epigenetic changes such as histone acetylation modification may play a role in the regulation of mda-7 expression, but there are no related studies. In this study, we demonstrated that histone deacetylase inhibitor TSA and NaBu could activate the expression of mda-7, and histone deacetylase 4 (HDAC4) could partially reverse this effect. It was also found that the level of histone acetylation at the promoter of mda-7 decreased after overexpression of HDAC4 and inhibited the binding of transcription factor Sp1 to mda-7 promoter. In addition, histone deacetylase inhibitor TSA induces histone hyperacetylation, promotes the binding of Sp1 to mda-7 promoter and activates the expression of mda-7. Therefore, we conclude that histone acetylation plays an important role in the regulation of mda-7 expression, and the transcription factor Sp1 is involved in this process.
【学位授予单位】：东北师范大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R739.5

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