Sox4 通过控制 Ezh2 的表达和表观遗传重编程来充当上皮-间充质转化的主调控因子。

Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming.

机构信息

Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.

出版信息

Cancer Cell. 2013 Jun 10;23(6):768-83. doi: 10.1016/j.ccr.2013.04.020.

DOI:10.1016/j.ccr.2013.04.020

Abstract

Gene expression profiling has uncovered the transcription factor Sox4 with upregulated activity during TGF-β-induced epithelial-mesenchymal transition (EMT) in normal and cancerous breast epithelial cells. Sox4 is indispensable for EMT and cell survival in vitro and for primary tumor growth and metastasis in vivo. Among several EMT-relevant genes, Sox4 directly regulates the expression of Ezh2, encoding the Polycomb group histone methyltransferase that trimethylates histone 3 lysine 27 (H3K27me3) for gene repression. Ablation of Ezh2 expression prevents EMT, whereas forced expression of Ezh2 restores EMT in Sox4-deficient cells. Ezh2-mediated H3K27me3 marks associate with key EMT genes, representing an epigenetic EMT signature that predicts patient survival. Our results identify Sox4 as a master regulator of EMT by governing the expression of the epigenetic modifier Ezh2.

摘要

基因表达谱分析揭示了转录因子 Sox4，其在正常和癌变乳腺上皮细胞中的 TGF-β 诱导的上皮-间充质转化（EMT）过程中活性上调。Sox4 对于 EMT 和细胞存活是不可或缺的，并且对于体内原发性肿瘤生长和转移也是不可或缺的。在几个 EMT 相关基因中，Sox4 直接调节编码 Polycomb 组组蛋白甲基转移酶的 Ezh2 的表达，该酶对组蛋白 3 赖氨酸 27（H3K27me3）进行三甲基化以抑制基因表达。Ezh2 表达的缺失可阻止 EMT，而强制表达 Ezh2 可恢复 Sox4 缺陷细胞中的 EMT。Ezh2 介导的 H3K27me3 标记与关键 EMT 基因相关联，代表预测患者生存的表观遗传 EMT 特征。我们的研究结果表明，Sox4 通过调节表观遗传修饰因子 Ezh2 的表达来充当 EMT 的主调控因子。