Epigenetic regulation of epithelial-mesenchymal transition by KDM6A histone demethylase in lung cancer cells

Abstract Histone methylationis associated with various biological and pathological processes including cancer development. KDM6A is a candidate tumor suppressor gene that encodes a histone H3lysine 27 (H3K27) demethylase. In this study, we discovered that ectopic expressionof KDM6A antagonized TGF-β-induced epithelial-mesenchymal transition(EMT) and cell migration of lung cancer cell lines through its demethylaseactivity. KDM6A counteracted TGF-β-dependent changes in the expression of EMT-related genes such as CDH1/E-cadherin , FN1/Fibronectin , ZEB family and microRNA-200 family. Mechanistic investigations revealed that KDM6A inhibited the recruitment of EZH2histone H3K27 methyltransferase and H3K27 methylation on the regulatory regions of the target genes such as CDH1and microRNA-200 family. Knockdown of KDM6A did not proceed EMT by itself, but influenced the expression of specific target genes critical for EMT, suggesting that endogenous KDM6A was involved in EMT-inducing transcriptional program. This study demonstrated a novel regulatory role of KDM6A histone demethylasein the epigenetic control of EMT process in lung cancer cells.