While the epithelial-mesenchymal transition (EMT) plays a fundamental role during development, its deregulation can adversely promote tumor metastasis. The phenotypic and cellular plasticity of EMT indicates that it is subject to epigenetic regulation. A hallmark of EMT is E-cadherin suppression. In this review, we try to embrace recent findings on the transcription factor Snail-mediated epigenetic silencing of E-cadherin. Our studies as well as those of others independently demonstrated that Snail can recruit various epigenetic machineries to the E-cadherin promoter. Based on these results, we propose a model of epigenetic regulation of EMT governed by Snail. Briefly, recruitment of the LSD1/HDAC complex by Snail facilitates histone H3K4 demethylation and H3/H4 deacetylation. Histone deacetylation may promote subsequent recruitment of PRC2 to methylate H3K27, while H3K4 demethylation favors the association of H3K9 methyltransferases G9a and Suv39H1. Finally, DNA methyltransferases (DNMTs) can be recruited to the promoter area in a G9a/Suv39H1-dependent manner. Together, these chromatin-modifying enzymes function in a Snail-mediated, highly orchestrated fashion to suppress E-cadherin. Disruption of the connection between Snail and these epigenetic machineries may represent an efficient strategy for the treatment of EMT-related diseases, including tumor metastasis.

译文

:尽管上皮-间质转化(EMT)在发育过程中起着基本作用,但其失调会不利地促进肿瘤转移。 EMT的表型和细胞可塑性表明它受到表观遗传调控。 EMT的标志是抑制E-钙黏着蛋白。在这篇综述中,我们尝试包含关于转录因子Snail介导的E-cadherin沉默的最新发现。我们的研究以及其他人的研究独立证明,Snail可以为E-cadherin启动子募集各种表观遗传机制。基于这些结果,我们提出了由Snail控制的EMT的表观遗传调控模型。简而言之,通过Snail募集LSD1 / HDAC复合物有助于组蛋白H3K4脱甲基和H3 / H4脱乙酰。组蛋白去乙酰化可能促进随后募集PRC2来甲基化H3K27,而H3K4去甲基化则有利于H3K9甲基转移酶G9a和Suv39H1的缔合。最后,可以以G9a / Suv39H1依赖的方式将DNA甲基转移酶(DNMT)募集到启动子区域。这些染色质修饰酶一起以Snail介导的,高度协调的方式发挥功能,以抑制E-钙黏着蛋白。破坏Snail和这些表观遗传机制之间的联系可能代表一种有效的策略,用于治疗EMT相关疾病,包括肿瘤转移。

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