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

[摘要] Transforming growth factor-beta (TGF-beta) signaling plays fundamental roles in the development and homeostasis of somatic cells. Dysregulated TGF-beta 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-beta-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-beta. 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-beta induced expression of MICAL1 and 2, and the histone demethylase, KDM7A, and revealed their regulatory roles on TGF-beta-induced cell migration. We also show a critical effect of KDM7A in regulating the acetylation of H3K27 on TGF-beta-induced genes. In sum, this study identified novel effectors that mediate the pro-migratory role of TGF-beta signaling, paving the way for future studies that investigate the function of MICAL family members in cancer and the novel epigenetic mechanisms downstream TGF-beta signaling.

[发布日期] 2019-12-01

[关键词] TGF-beta;Migration;MICAL1;KDM7A/JHDM1D;Epigenetics