title: Resveratrol limits epithelial to mesenchymal transition through modulation of KHSRP/hnRNPA1-dependent alternative splicing in mammary gland cells.
abstract: 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.
authors.affiliation: Gene Expression Regulation Laboratory, IRCCS AOU San Martino-IST, 16132, Genova, Italy; DIMES Sez. Biochimica-Università di Genova, 16132, Genova, Italy; Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Arfa
authors.initials: A
authors.lastname: Moshiri
authors.affiliation: Gene Expression Regulation Laboratory, IRCCS AOU San Martino-IST, 16132, Genova, Italy; Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Margherita
authors.initials: M
authors.lastname: Puppo
authors.affiliation: Gene Expression Regulation Laboratory, IRCCS AOU San Martino-IST, 16132, Genova, Italy; Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Martina
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Gene Expression Regulation Laboratory, IRCCS AOU San Martino-IST, 16132, Genova, Italy. Electronic address: rgherzi@ucsd.edu.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gherzi
authors.affiliation: Gene Expression Regulation Laboratory, IRCCS AOU San Martino-IST, 16132, Genova, Italy. Electronic address: paola.briata@hsanmartino.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Briata
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects*; D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: C476399:Cd44 protein, mouse; D003598:Cytoskeletal Proteins; C102176:Enah protein, mouse; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C000619657:Hnrnpa1 protein, mouse; D018960:Hyaluronan Receptors; D008840:Microfilament Proteins; D016601:RNA-Binding Proteins; D013267:Stilbenes; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2; D000077185:Resveratrol
keywords: Alternative splicing; Epithelial to mesenchymal transition; RNA-Binding Proteins; Resveratrol