title: The microbe-derived short chain fatty acid butyrate targets miRNA-dependent p21 gene expression in human colon cancer.
abstract: Colonic microbiota ferment non-absorbed dietary fiber to produce prodigious amounts of short chain fatty acids (SCFAs) that benefit the host through a myriad of metabolic, trophic, and chemopreventative effects. The chemopreventative effects of the SCFA butyrate are, in part, mediated through induction of p21 gene expression. In this study, we assessed the role of microRNA(miRNA) in butyrate's induction of p21 expression. The expression profiles of miRNAs in HCT-116 cells and in human sporadic colon cancers were assessed by microarray and quantitative PCR. Regulation of p21 gene expression by miR-106b was assessed by 3' UTR luciferase reporter assays and transfection of specific miRNA mimics. Butyrate changed the expression of 44 miRNAs in HCT-116 cells, many of which were aberrantly expressed in colon cancer tissues. Members of the miR-106b family were decreased in the former and increased in the latter. Butyrate-induced p21 protein expression was dampened by treatment with a miR-106b mimic. Mutated p21 3'UTR-reporter constructs expressed in HCT-116 cells confirmed direct miR-106b targeting. Butyrate decreased HCT-116 proliferation, an effect reversed with the addition of the miR-106b mimic. We conclude that microbe-derived SCFAs regulate host gene expression involved in intestinal homeostasis as well as carcinogenesis through modulation of miRNAs.
authors.affiliation: The Martin Boyer Laboratories, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Shien
authors.initials: S
authors.lastname: Hu
authors.forename: Tien Sy
authors.initials: TS
authors.lastname: Dong
authors.forename: Sushila R
authors.initials: SR
authors.lastname: Dalal
authors.forename: Feng
authors.initials: F
authors.lastname: Wu
authors.forename: Marc
authors.initials: M
authors.lastname: Bissonnette
authors.forename: John H
authors.initials: JH
authors.lastname: Kwon
authors.forename: Eugene B
authors.initials: EB
authors.lastname: Chang
mesh_terms: D002087:Butyrates / Q000494:pharmacology*; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors* / Q000235:genetics; D005232:Fatty Acids, Volatile / Q000494:pharmacology*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D002087:Butyrates; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005232:Fatty Acids, Volatile; C542541:MIRN106 microRNA, human; D035683:MicroRNAs