Requirement of the histone demethylase LSD1 in Snai1-mediated transcriptional repression during epithelial-mesenchymal transition.
Requirement of the histone demethylase LSD1 in Snai1-mediated transcriptional repression during epithelial-mesenchymal transition.
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DOI：
10.1038/onc.2010.234
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发表时间：
2010-09-02
期刊：
影响因子：
8
通讯作者：
Lu, J.
中科院分区：
文献类型：
--
作者：
Lin, T.;Ponn, A.;Hu, X.;Law, B. K.;Lu, J.
上皮-间充质转化(EMT)在胚胎发育和肿瘤进展中起着关键作用。Snail锌指转录因子家族成员是EMT的中枢调节因子，部分通过直接抑制上皮性标志物如E-钙粘附素诱导EMT，E-钙粘附素是上皮表型的守门人，也是肿瘤侵袭的抑制因子。然而，Snai1(Snail)介导转录抑制的分子机制仍不完全清楚。在这里，我们证明了Snai1与组蛋白去甲基酶LSD1(KDM1A)物理上相互作用并招募到上皮基因启动子。LSD1去除组蛋白H3(H3K4m2)上赖氨酸4的二甲基化，组蛋白H3是一种与活性染色质相关的共价组蛋白修饰。重要的是，LSD1对于Snai1介导的转录抑制和在侵袭性癌细胞中维持Snai1靶基因的沉默状态是必不可少的。在LSD1缺失的情况下，Snai1不能抑制E-钙粘附素。在E-钙粘蛋白沉默的癌细胞中，LSD1的缺失导致上皮基因的部分抑制，并提高了E-钙粘素启动子上的H3K4m2水平。这些结果强调了LSD1在Snai1依赖的上皮标志物转录抑制中的关键作用，并提示LSD1复合体可能是预防肿瘤侵袭的潜在治疗靶点。
Epithelial-mesenchymal transition (EMT) plays pivotal roles during embryonic development and carcinoma progression. Members of the Snail family of zinc finger transcription factors are central mediators of EMT and induce EMT in part by directly repressing epithelial markers such as E-cadherin, a gatekeeper of the epithelial phenotype and a suppressor of tumor invasion. However, the molecular mechanism underlying Snai1 (Snail)-mediated transcriptional repression remains incompletely understood. Here we show that Snai1 physically interacts with and recruits the histone demethylase LSD1 (KDM1A) to epithelial gene promoters. LSD1 removes dimethylation of lysine 4 on histone H3 (H3K4m2), a covalent histone modification associated with active chromatin. Importantly, LSD1 is essential for Snai1-mediated transcriptional repression and for maintenance of the silenced state of Snai1 target genes in invasive cancer cells. In the absence of LSD1, Snai1 fails to repress E-cadherin. In cancer cells in which E-cadherin is silenced, depletion of LSD1 results in partial de-repression of epithelial genes and elevated H3K4m2 levels at the E-cadherin promoter. These results underline the critical role of LSD1 in Snai1-dependent transcriptional repression of epithelial markers and suggest that the LSD1 complex may be a potential therapeutic target for prevention of tumor invasion.
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