State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha, Hunan 410082, China.
Department of Pathology, Hunan Provincial Tumor Hospital, Changsha, Hunan 410013, China.
Cancer Lett. 2015 Jun 1;361(2):240-50. doi: 10.1016/j.canlet.2015.03.008. Epub 2015 Mar 14.
The Forkhead Box A2 (FOXA2) transcription factor is required for embryonic development and for normal functions of multiple adult tissues, in which the maintained expression of FOXA2 is usually related to preventing the progression of malignant transformation. In this study, we found that FOXA2 prevented the epithelial to mesenchymal transition (EMT) in human breast cancer. We observed a strong correlation between the expression levels of FOXA2 and the epithelial phenotype. Knockdown of FOXA2 promoted the mesenchymal phenotype, whereas stable overexpression of FOXA2 attenuated EMT in breast cancer cells. FOXA2 was found to endogenously bind to and stimulate the promoter of E-cadherin that is crucial for epithelial phenotype of the tumor cells. Meanwhile, FOXA2 prevented EMT of breast cancer cells by repressing the expression of EMT-related transcription factor ZEB2 through recruiting a transcriptional corepressor TLE3 to the ZEB2 promoter. The stable overexpression of FOXA2 abolished metastasis of breast cancer cells in vivo. This study confirmed that FOXA2 inhibited EMT in breast cancer cells by regulating the transcription of EMT-related genes such as E-cadherin and ZEB2.
叉头框蛋白 A2（FOXA2）转录因子对于胚胎发育和多种成年组织的正常功能是必需的，在这些组织中，FOXA2 的持续表达通常与防止恶性转化的进展有关。在这项研究中，我们发现 FOXA2 可防止人乳腺癌中的上皮间质转化（EMT）。我们观察到 FOXA2 的表达水平与上皮表型之间存在很强的相关性。FOXA2 的敲低促进了间充质表型，而 FOXA2 的稳定过表达则减弱了乳腺癌细胞的 EMT。FOXA2 被发现可内源性结合并刺激 E-钙粘蛋白启动子，E-钙粘蛋白对于肿瘤细胞的上皮表型至关重要。同时，FOXA2 通过招募转录核心抑制子 TLE3 到 ZEB2 启动子来抑制 EMT 相关转录因子 ZEB2 的表达，从而防止乳腺癌细胞的 EMT。FOXA2 的稳定过表达可消除体内乳腺癌细胞的转移。这项研究证实，FOXA2 通过调节 EMT 相关基因如 E-钙粘蛋白和 ZEB2 的转录来抑制乳腺癌细胞中的 EMT。
