FOXC1 Regulates FGFR1 Isoform Switching to Promote Invasion Following TGFβ-Induced EMT

Epithelial-to-mesenchymal transition (EMT) is an important physiologic process that drives tissue formation during development, but also contributes to disease pathogenesis, including fibrosis and cancer metastasis. Elevated expression of the FOXC1 transcription factor has been detected in several metastatic cancers that have undergone EMT. Therefore, mechanistic insight into the role of FOXC1 in the initiation of the EMT process was sought. It was determined that although Foxc1 transcript expression was elevated following TGFβ1-induced EMT of NMuMG cells, FOXC1 was not required for this induction. RNA sequencing revealed that the mRNA levels of FGF receptor 1-isoform IIIc (Fgfr1-IIIc), normally activated upon TGFβ1 treatment, were reduced in Foxc1 knockdown cells, and overexpression of Foxc1 was sufficient to induce Fgfr1-IIIc expression, but not EMT. Chromatin immunoprecipitation experiments demonstrated that FOXC1 binds to an Fgfr1 upstream regulatory region and that FOXC1 activates an Fgfr1 promoter element. Furthermore, elevated expression of Foxc1 led to increased Fgfr1-IIIc transcript. Foxc1 knockdown impaired the FGF2-mediated three-dimensional migratory ability of NMuMG cells, which was rescued by expression of FGFR1. In addition, elevated expression of FOXC1 and FGFR1 was also observed in migratory mesenchymal MDA-MB-231 breast cancer cells. Together, these results define a role for FOXC1 in specifying an invasive mesenchymal cell type by promoting FGFR1 isoform switching following induction of TGFβ1-mediated EMT. Mol Cancer Res; 15(10); 1341-53. ©2017 AACR.