Identification of novel TGF-β regulated genes with pro-migratory roles.

Transforming growth factor-β (TGF-β) signaling plays fundamental roles in the development and homeostasis of somatic cells. Dysregulated TGF-β signaling contributes to cancer progression and relapse to therapies by inducing epithelial-to-mesenchymal transition (EMT)， enriching cancer stem cells， and promoting immunosuppression. Although many TGF-β-regulated genes have been identified， only a few datasets were obtained by next-generation sequencing. In this study， we performed RNA-sequencing analysis of MCF10A cells and identified 1166 genes that were upregulated and 861 genes that were downregulated by TGF-β. Gene set enrichment analysis revealed that focal adhesion and metabolic pathways were the top enriched pathways of the up- and downregulated genes， respectively. Genes in these pathways also possess significant predictive value for renal cancers. Moreover， we confirmed that TGF-β induced expression of MICAL1 and 2， and the histone demethylase， KDM7A， and revealed their regulatory roles on TGF-β-induced cell migration. We also show a critical effect of KDM7A in regulating the acetylation of H3K27 on TGF-β-induced genes. In sum， this study identified novel effectors that mediate the pro-migratory role of TGF-β signaling， paving the way for future studies that investigate the function of MICAL family members in cancer and the novel epigenetic mechanisms downstream TGF-β signaling.