title: Cell type- and promoter-dependent modulation of the Wnt signaling pathway by sodium butyrate.
abstract: The Wnt signaling pathway modulates the transcription of genes linked to proliferation, differentiation and tumor progression. beta-Catenin-Tcf (BCT)-dependent Wnt signaling is influenced by the short-chain fatty acid sodium butyrate, which induces growth arrest and/or maturation of colonic carcinoma cells. We have compared the effects of sodium butyrate on BCT-dependent signaling in 2 colon carcinoma cell lines that differ in their physiologic response to butyrate, with SW620 cells responding to butyrate by undergoing terminal differentiation and apoptosis, and HCT-116 cells undergoing reversible growth arrest, but no significant apoptotic cell death. Furthermore, these colon carcinoma cell lines differ in their mechanism of Wnt pathway activation, with adenomatous polyposis coli (APC) mutant SW620 cells having high levels of BCT complexes and APC wild-type HCT-116 cells having mutant beta-catenin, low levels of BCT complexes and correspondingly higher levels of free Tcf. We have demonstrated that in SW620 cells, butyrate downregulates BCT-dependent expression of the Tcf-TK, matrilysin and cyclin D1 promoters, whereas in HCT-116 cells, butyrate upregulates expression of these promoters. Cotransfection with expression vectors that interfere with the Wnt pathway suggests that butyrate enhances BCT complex-DNA binding. Butyrate reduces the expression of Tcf4 in HCT-116 cells, consistent with the induction by butyrate of Tcf-repressible promoters in these cells. These findings indicate that sodium butyrate modulates the Wnt pathway in SW620 and HCT-116 cells in a different manner and that these differences have consequences for promoter activity that may influence the physiologic response to butyrate.
authors.affiliation: Department of Pharmacology and Developmental Therapeutics Section, Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA. michaelbordonaro@yahoo.com
authors.forename: Michael
authors.initials: M
authors.lastname: Bordonaro
authors.forename: Darina L
authors.initials: DL
authors.lastname: Lazarova
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Augenlicht
authors.forename: Alan C
authors.initials: AC
authors.lastname: Sartorelli
mesh_terms: D001665:Binding Sites; D002087:Butyrates / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020783:Matrix Metalloproteinase 7 / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
chemical_list: D002087:Butyrates; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D011518:Proto-Oncogene Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D019938:Cyclin D1; C012589:trichostatin A; D020783:Matrix Metalloproteinase 7