Suppressive Role Of KLF5on Induced Epithelial-Mesenchymal Transition In Both Normal And Cancerous Epithelial Cells

KLF5(Kruppel-like factor5) is a basic transcriptional factor that regulates a number of physiopathological processes. Current literature and bioinformatic analyses suggest that KLF5could also modulate the epithelial-to-mesenchymal transition (EMT), yet the possibility and the underlying mechanisms of which have not been determined. In this study, we tested whether and how KLF5regulates epithelial-to-mesenchymal transition (EMT) in both normal and cancerous epithelial cells. In these epithelial cells, we found that KLF5was downregulated during EMT induced by TGF-β (and EGF) treatment and that knockdown of KLF5induced EMT as indicated by phenotypic and molecular EMT properties such as altering the cell morphology, enhancing the migration (and invasion) ability, and causing the down-regulation of epithelial markers including E-cadherin and ZO1, the up-regulation of mesenchymal markers such as FN1and Vimentin, as well as the dislocation of CDH1and F-actin. Array-based, screening suggested, and biochemical analyses confirmed, that the miR-200miRNAs, a group of well-established EMT repressors, were transcriptionally activated by KLF5via its direct binding to the GC boxes in miR-200gene promoters. Functionally, overexpression of miR-200prevented the EMT induced by KLF5knockdown or by TGF-β/EGF treatment and ectopic expression of KLF5attenuated induced EMT in both normal and cancerous epithelial cells. In prostate cancer cells, deregulation of KLF5influenced prostate cancer stem-like properties, which are closely linked to EMT in cancer. Furthermore, results from DU145xenografts supported KLF5as a suppressor of both EMT and prostate cancer sternness. In mouse prostates, knockout of Klf5downregulated the miR-200family and induced molecular changes indicative of EMT. Correlation analysis in breast cancer provided evidence that KLF5was correlated with miR-200expression. These findings indicate that KLF5maintains epithelial characteristics and prevents EMT by transcriptionally activating the miR-200family in both normal and cancerous epithelial cells, and reveal one new mechanism underlying the EMT induced by TGF-β. The KLF5-miR-200axis could modulate multiple pathological and physiological processes by regulating cellular EMT-MET plasticity, including cell migration, sternness, iPSC generation, tumorigenesis and metastasis, and development.