Liu Yuxiang, Chen Taolin, Guo Mingyue, Li Yu, Zhang Qian, Tan Guixiang, Yu Li, Tan Yongjun
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan Engineering Research Center for Anticancer Targeted Protein Pharmaceuticals, Hunan University, Changsha, China.
Front Oncol. 2021 Feb 25;11:605025. doi: 10.3389/fonc.2021.605025. eCollection 2021.
FOXP2, a member of forkhead box transcription factor family, was first identified as a language-related gene that played an important role in language learning and facial movement. In addition, FOXP2 was also suggested regulating the progression of cancer cells. In previous studies, we found that FOXA2 inhibited epithelial-mesenchymal transition (EMT) in breast cancer cells. In this study, by identifying FOXA2-interacting proteins from FOXA2-pull-down cell lysates with Mass Spectrometry Analysis, we found that FOXP2 interacted with FOXA2. After confirming the interaction between FOXP2 and FOXA2 through Co-IP and immunofluorescence assays, we showed a correlated expression of FOXP2 and FOXA2 existing in clinical breast cancer samples. The overexpression of FOXP2 attenuated the mesenchymal phenotype whereas the stable knockdown of FOXP2 promoted EMT in breast cancer cells. Even though FOXP2 was believed to act as a transcriptional repressor in most cases, we found that FOXP2 could activate the expression of tumor suppressor PHF2. Meanwhile, we also found that FOXP2 could endogenously bind to the promoter of E-cadherin and activate its transcription. This transcriptional activity of FOXP2 relied on its interaction with FOXA2. Furthermore, the stable knockdown of FOXP2 enhanced the metastatic capacity of breast cancer cells . Together, the results suggested that FOXP2 could inhibit EMT by activating the transcription of certain genes, such as E-cadherin and PHF2, in concert with FOXA2 in breast cancer cells.
FOXP2是叉头框转录因子家族的成员之一，最初被鉴定为一种与语言相关的基因，在语言学习和面部运动中发挥重要作用。此外，FOXP2也被认为参与调控癌细胞的进展。在之前的研究中，我们发现FOXA2抑制乳腺癌细胞的上皮-间质转化（EMT）。在本研究中，通过质谱分析从FOXA2下拉细胞裂解物中鉴定与FOXA2相互作用的蛋白质，我们发现FOXP2与FOXA2相互作用。通过免疫共沉淀（Co-IP）和免疫荧光试验证实FOXP2与FOXA2之间的相互作用后，我们发现临床乳腺癌样本中存在FOXP2和FOXA2的相关性表达。FOXP2的过表达减弱了间充质表型，而FOXP2的稳定敲低促进了乳腺癌细胞的EMT。尽管在大多数情况下FOXP2被认为是一种转录抑制因子，但我们发现FOXP2可以激活肿瘤抑制因子PHF2的表达。同时，我们还发现FOXP2可以内源性结合E-钙黏蛋白的启动子并激活其转录。FOXP2的这种转录活性依赖于其与FOXA2的相互作用。此外，FOXP2的稳定敲低增强了乳腺癌细胞的转移能力。总之，结果表明FOXP2可以与FOXA2协同作用，通过激活某些基因（如E-钙黏蛋白和PHF2）的转录来抑制乳腺癌细胞的EMT。
