DACH1 inhibits SNAI1-mediated epithelial-mesenchymal transition and represses breast carcinoma metastasis.
DACH1 inhibits SNAI1-mediated epithelial-mesenchymal transition and represses breast carcinoma metastasis.
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DOI：
10.1038/oncsis.2015.3
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发表时间：
2015-03-16
期刊：
影响因子：
6.2
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Zhao F;Wang M;Li S;Bai X;Bi H;Liu Y;Ao X;Jia Z;Wu H
上皮-间质转化（EMT）在癌症进展和转移中起重要作用。然而，这一过程中涉及的转录抑制的具体机制在很大程度上仍然未知。Dachshund同源物1（DACH 1）表达在浸润性乳腺癌中丢失，预后不良，DACH 1在调节乳腺癌转移中的作用知之甚少。在本研究中，DACH 1的表达和乳腺癌细胞的形态学之间的显着相关性进行了观察。随后对DACH 1和EMT之间关系的研究表明，在ZR-75-30细胞中过表达DACH 1诱导上皮形态和细胞-细胞粘附的转变，以及增加上皮标志物E-cadherin的表达并抑制细胞迁移和侵袭。相反，在MCF-7和T47 D细胞中沉默DACH 1破坏了上皮形态和细胞-细胞接触，降低了E-cadherin的表达，并诱导细胞迁移和侵袭。DACH 1也与SNAI 1特异性相互作用，但不与SNAI 2相互作用，形成复合物，该复合物可以以SNAI 1依赖的方式与E-cadherin启动子上的E-box结合。DACH 1抑制SNAI 1的转录活性，导致乳腺癌细胞中E-cadherin的激活。此外，在小鼠模型中，DACH 1的水平也与转移的程度相关。DACH 1过表达可显著抑制4 T1/Luc细胞在BALB/c小鼠体内的生长和转移。对取自人类乳腺癌的组织样本的分析显示，在SNAI 1阳性乳腺癌中，DACH 1和E-cadherin的表达之间存在显著相关性。总的来说，我们的数据确定了一种新的机制途径，用于调节EMT和乳腺癌细胞的转移，一种是基于通过直接DACH 1-SNAI 1相互作用调节E-钙粘蛋白表达。
Epithelial–mesenchymal transition (EMT) has a major role in cancer progression and metastasis. However, the specific mechanism of transcriptional repression involved in this process remains largely unknown. Dachshund homologue 1 (DACH1) expression is lost in invasive breast cancer with poor prognosis, and the role of DACH1 in regulating breast cancer metastasis is poorly understood. In this study, significant correlation between the expression of DACH1 and the morphology of breast cancer cells was observed. Subsequent investigation into the relationship between DACH1 and EMT showed that overexpression of DACH1 in ZR-75-30 cells induced a shift towards epithelial morphology and cell–cell adhesion, as well as increased the expression of the epithelial marker E-cadherin and suppressed cell migration and invasion. In contrast, silencing DACH1 in MCF-7 and T47D cells disrupted the epithelial morphology and cell–cell contact, reduced the expression of E-cadherin, and induced cell migration and invasion. DACH1 also specifically interacted with SNAI1, but not SNAI2, to form a complex, which could bind to the E-box on the E-cadherin promoter in an SNAI1-dependent manner. DACH1 inhibited the transcriptional activity of SNAI1, leading to the activation of E-cadherin in breast cancer cells. Furthermore, the level of DACH1 also correlated with the extent of metastasis in a mouse model. DACH1 overexpression significantly decreased the metastasis and growth of 4T1/Luc cells in BALB/c mice. Analysis of tissue samples taken from human breast cancers showed a significant correlation between the expression of DACH1 and E-cadherin in SNAI1-positive breast cancer. Collectively, our data identified a new mechanistic pathway for the regulation of EMT and metastasis of breast cancer cells, one that is based on the regulation of E-cadherin expression by direct DACH1–SNAI1 interaction.