Resveratrol limits epithelial to mesenchymal transition through modulation of KHSRP/hnRNPA1-dependent alternative splicing in mammary gland cells

Resveratrol (RESV) is a natural polyphenolic compound endowed with anti-inflammatory, anti-proliferative, as well as pro-apoptotic activities that make it a potential anti-tumor compound. Here we show that RESV counteracts the TGF-β-induced Epithelial to Mesenchymal Transition (EMT) phenotype in mammary gland cells and affects the alternative exon usage of pre-mRNAs that encode crucial factors in adhesion and migration -including CD44, ENAH, and FGFR2- in a panel of immortalized and transformed mammary gland cells. RESV causes a shift from the mesenchymal-specific forms of these factors to the respective epithelial forms and increases the expression of the RNA-binding proteins KHSRP and hnRNPA1. From a mechanistic point of view, we show that the combined silencing of KHSRP and hnRNPA1 prevents the RESV-dependent inclusion of the epithelial-type exons in the Cd44 pre-mRNA. Our findings support an unexpected regulatory mechanism where RESV limits EMT by controlling gene expression at post-transcriptional level.