Abstract
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 in vivo. 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.
Highlights
Breast cancer is the most common malignant tumor and the leading cause of cancer death among women [1]
We found that FOXP2 and FOXA2 together formed complexes binding to the DNA probe but FOXA2 alone could not bind to the probe (Figure 4D), implicating that the mechanism of FOXP2 stimulating the E-cadherin transcription might involve its interaction with FOXA2
epithelialmesenchymal transition (EMT) plays an important role in breast cancer metastasis and in addition, activation of an EMT program enables normal and neoplastic epithelial cells to acquire stem like properties
Summary
Breast cancer is the most common malignant tumor and the leading cause of cancer death among women [1]. One of the important mechanisms regulating the invasive behavior of cancer cells is the epithelialmesenchymal transition (EMT), which represents the conversion of differentiated epithelial cancer. FOXP2 Inhibits EMT of Breast Cancer cells into migratory mesenchymal cancer cells, leading to cancer invasion, systemic cancer cell dissemination and metastasis [3]. EMT results in cancer cells avoiding cellular senescence and apoptosis, and participates in the generation and maintenance of cancer stem cells [4], highly consistent with the ability of metastatic cells to initiate new tumors [5]. During the progress of EMT, the expression of epithelial markers such as the junction protein E-cadherin is lost and the expression of mesenchymal markers such as Vimentin is up-regulated in cancer cells [6]. Gene expression profiling experiments of EMT suggest that many genes adjust in their expression during EMT [7], regulated by a network of signaling pathways from a variety of growth factors [i.e., epidermal growth factor (EGF) [8]] and multiple transcription factors [9, 10]
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