DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells
DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells
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DOI：
10.1038/sj.onc.1208429
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发表时间：
2005-03-31
期刊：
影响因子：
8
通讯作者：
Foisner, R
中科院分区：
文献类型：
--
作者：
Eger, A;Aigner, K;Foisner, R
E-钙粘附素的下调是胚胎发育和肿瘤进展中上皮向间充质转化(EMT)的关键事件。使用EpFoser乳腺肿瘤模型，我们表明在EMT期间，转录调节因子DeltaEF1的上调与E-钙粘素的转录抑制相一致。DeltaEF1在上皮细胞中的异位表达足以下调E-钙粘蛋白并诱导EMT。E-钙粘蛋白启动子活性分析和染色质免疫沉淀分析表明，deltaEF1是E-钙粘蛋白的直接转录抑制因子。在人类癌细胞中，DeltaEF1的转录水平与E-钙粘素抑制的程度和上皮表型的丧失直接相关。该蛋白富含在人类癌细胞的细胞核中，并与E-钙粘附素启动子有物理联系。RNA干扰介导的DeltaEF1在癌细胞中的下调足以降低E-钙粘附素的表达，并恢复细胞与细胞的黏附，提示DeltaEF1在晚期癌症发生中起关键作用。
Downregulation of E-cadherin is a crucial event for epithelial to mesenchymal transition (EMT) in embryonic development and cancer progression. Using the EpFosER mammary tumour model we show that during EMT, upregulation of the transcriptional regulator deltaEF1 coincided with transcriptional repression of E-cadherin. Ectopic expression of deltaEF1 in epithelial cells was sufficient to downregulate E-cadherin and to induce EMT. Analysis of E-cadherin promoter activity and chromatin immunoprecipitation identified deltaEF1 as direct transcriptional repressor of E-cadherin. In human cancer cells, transcript levels of deltaEF1 correlated directly with the extent of E-cadherin repression and loss of the epithelial phenotype. The protein was enriched in nuclei of human cancer cells and physically associated with the E-cadherin promoter. RNA interference-mediated downregulation of deltaEF1 in cancer cells was sufficient to derepress E-cadherin expression and restore cell to cell adhesion, suggesting that deltaEF1 is a key player in late stage carcinogenesis.