FoxC1 promotes epithelial-mesenchymal transition through PBX1 dependent transactivation of ZEB2 in esophageal cancer.

Esophageal cancer (EC) was one of the most lethal malignancies worldwide with intricate mechanisms. Here we reported that Forkhead box C1 (FoxC1), a member of the forkhead family transcription factors, was up-regulated in EC tissues and cell lines in comparison with controls. FoxC1 levels were negatively correlated with tumor stage, lymph node metastasis and survival status of EC patients. Knockdown of FoxC1 inhibited the proliferation, colony formation and epithelial-mesenchymal transition (EMT) of EC cells, while overexpression of FoxC1 promoted these biological behaviors. Mechanically, serial deletion and chromatin immunoprecipitation assays showed that ZEB2, a well-reported transcriptional suppressor of E-cadherin, was a direct transcriptional target of FoxC1. Moreover, FoxC1 was recruited to the ZEB2 promoter by its interaction with the pioneer transcription factor pre-B-cell leukemia homeobox 1 (PBX1). Importantly, significant correlation between levels of FoxC1 and ZEB2 was observed in EC tissues and the two proteins could be used as prognostic biomarkers together. Hence, our results revealed a critical role of FoxC1 in the EMT process of EC and uncovered a novel mechanism for the regulation of ZEB2-E-cadherin axis in EC.