MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition
MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition
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DOI：
10.1016/j.celrep.2016.05.050
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发表时间：
2016-06-21
期刊：
影响因子：
8.8
通讯作者：
Lu, Jianrong
中科院分区：
文献类型：
--
作者：
Luo, Huacheng;Shenoy, Anitha K.;Lu, Jianrong
组蛋白去甲基化酶LSD1通过抑制上皮标志物表达促进上皮向间质转化（EMT）和肿瘤进展。然而，很少有人知道它的功能是如何调制的。在这里，我们报告说，LSD1是乙酰化的上皮细胞，但不是间充质细胞。LSD 1的乙酰化降低了其与核小体的结合，从而增加了其靶基因处的组蛋白H3K4甲基化并激活转录。MOF乙酰转移酶与LSD 1相互作用并负责其乙酰化。MOF优先在上皮细胞中表达，并被EMT诱导信号下调。外源性MOF的表达阻碍LSD 1与上皮基因启动子的结合和组蛋白去甲基化，从而抑制EMT和肿瘤侵袭。相反，M0F缺失增强EMT和肿瘤转移。在人类癌症中，高MOF表达与上皮标志物和良好的预后相关。这些发现提供了对LSD1和EMT调控的深入了解，并将MOF确定为EMT和肿瘤进展的关键抑制因子。
The histone demethylase LSD1 facilitates epithelial-to-mesenchymal transition (EMT) and tumor progression by repressing epithelial marker expression. However, little is known about how its function may be modulated. Here, we report that LSD1 is acetylated in epithelial but not mesenchymal cells. Acetylation of LSD1 reduces its association with nucleosomes, thus increasing histone H3K4 methylation at its target genes and activating transcription. The MOF acetyltransferase interacts with LSD1 and is responsible for its acetylation. MOF is preferentially expressed in epithelial cells and is downregulated by EMT-inducing signals. Expression of exogenous MOF impedes LSD1 binding to epithelial gene promoters and histone demethylation, thereby suppressing EMT and tumor invasion. Conversely, MOFdepletion enhances EMT and tumor metastasis. In human cancer, high MOF expression correlates with epithelial markers and a favorable prognosis. These findings provide insight into the regulation of LSD1 and EMT and identify MOF as a critical suppressor of EMT and tumor progression.