FOXA2 functions as a suppressor of tumor metastasis by inhibition of EMT

On September 7, the Cell Research online published the latest findings of Prof. Jianguo Song’s group from SIBCB: Forkhead box transcription factor A2 (FOXA2) functions as a suppressor of tumor metastasis by inhibition of epithelial-to-mesenchymal transition in human lung cancers.

 

Tumor is known as one of the most dangerous threats to human health, and ~90% of all cancer deaths arise from the metastatic spread of primary tumors. It has been widely recognized that epithelial-to-mesenchymal transition (EMT) is one of the major mechanisms for carcinoma progression, and the most compelling evidence for the involvement of EMT in carcinogenesis is the ability of multiple EMT regulators to enhance tumor formation and/or metastasis. FOXA2 belongs to the forkhead box (FOX) gene superfamily. It is required for the formation of the node, notochord, nervous system, and endoderm-derived structures. Besides its importance in regulating embryo development, FOXA2 also plays a key role in metabolism. It regulates normal bile acid homeostasis and controls lipid homeostasis by affecting the clearance rate of fatty acids through oxidation and/or secretion of lipids in response to insulin. Although FOXA2 was found to be expressed in all types of neuroendocrine lung tumors, and was shown to be a key regulator in colorectal liver metastases, whether FOXA2 functions in human lung tumor development remains to be investigated. In this study, the researchers found that in human lung cancer cell lines, the abundance of FOXA2 positively correlates with epithelial phenotypes and negatively correlates with the mesenchymal phenotypes of cells, and TGF-β1 treatment decreased FOXA2 protein level. Consistently, knockdown of FOXA2 promoted EMT and invasion of lung cancer cells, whereas overexpression of FOXA2 reduced the invasion and suppressed TGF-β1-induced EMT. In addition, knockdown of FOXA2 induced slug expression, and ectopic expression of FOXA2 inhibited slug transcription. Furthermore, the scientists identified that FOXA2 can bind to slug promoter through a conserved binding site, and that the DNA-binding region and transactivation region II of FOXA2 are required for repression of the slug promoter. These data demonstrate that FOXA2 functions as a suppressor of tumor metastasis by inhibition of EMT.

 

This research was supported by grants from the Ministry of Science and Technology, National Natural Science Foundation of China, the National High-Tech Research and Development Program of China, and the Chinese Academy of Sciences.