Kruppel-like Factor 4 Inhibits Epithelial-to-Mesenchymal Transition through Regulation of E-cadherin Gene Expression
Kruppel-like Factor 4 Inhibits Epithelial-to-Mesenchymal Transition through Regulation of E-cadherin Gene Expression
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DOI：
10.1074/jbc.m110.114546
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发表时间：
2010-05-28
影响因子：
4.8
通讯作者：
Keri, Ruth A.
中科院分区：
文献类型：
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作者：
Yori, Jennifer L.;Johnson, Emhonta;Keri, Ruth A.
Kruppel 样因子 4 (KLF4) 是上皮细胞在发育和肿瘤发生过程中增殖和分化的转录调节因子。尽管 KLF4 在包括结肠在内的多种组织中发挥肿瘤抑制因子的作用，但 KLF4 在乳腺癌中的作用尚不清楚。在这里，我们表明 KLF4 对于维持未转化的 MCF-10A 乳腺上皮细胞中的上皮表型是必需的。 KLF4 沉默导致上皮细胞形态和迁移的改变，表明上皮细胞向间质细胞的转变。与这些变化一致，KLF4 水平降低也导致 E-钙粘蛋白和 mRNA 的丢失。启动子/报告基因分析显示，KLF4 沉默导致 E-钙粘蛋白启动子活性降低，而染色质免疫沉淀鉴定出内源性 KLF4 与该启动子的富含 GC/E-box 区域结合。此外，在高度转移的MDA-MB-231乳腺肿瘤细胞系中强制表达KLF4足以恢复E-钙粘蛋白的表达并抑制迁移和侵袭。这些发现将 E-钙粘蛋白确定为 KLF4 的新转录靶标。 KLF4 维持 E-钙粘蛋白表达和防止乳腺上皮细胞上皮间质转化的明确要求支持 KLF4 在乳腺癌中的转移抑制作用。
The Kruppel-like factor 4 (KLF4) is a transcriptional regulator of proliferation and differentiation in epithelial cells, both during development and tumorigenesis. Although KLF4 functions as a tumor suppressor in several tissues, including the colon, the role of KLF4 in breast cancer is less clear. Here, we show that KLF4 is necessary for maintenance of the epithelial phenotype in non-transformed MCF-10A mammary epithelial cells. KLF4 silencing led to alterations in epithelial cell morphology and migration, indicative of an epithelial-to-mesenchymal transition. Consistent with these changes, decreased levels of KLF4 also resulted in the loss of E-cadherin protein and mRNA. Promoter/reporter analyses revealed decreased E-cadherin promoter activity with KLF4 silencing, while chromatin immuno-precipitation identified endogenous KLF4 binding to the GC-rich/E-box region of this promoter. Furthermore, forced expression of KLF4 in the highly metastatic MDA-MB-231 breast tumor cell line was sufficient to restore E-cadherin expression and suppress migration and invasion. These findings identify E-cadherin as a novel transcriptional target of KLF4. The clear requirement for KLF4 to maintain E-cadherin expression and prevent epithelial-to-mesenchymal transition in mammary epithelial cells supports a metastasis suppressive role for KLF4 in breast cancer.