Cell type- and promoter-dependent modulation of the Wnt signaling pathway by sodium butyrate

The Wnt signaling pathway modulates the transcription of genes linked to pr oliferation, 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 carcino ma 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 rever sible growth arrest, but no significant apoptotic cell death. Furthermore, these colon carcinoma cell lines differ in their mechanism of Wnt pathway a ctivation, 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 level s of free Tcf. We have demonstrated that in SW620 cells, butyrate downregul ates BCT-dependent expression of the Tcf-TK, matrilysin and cyclin DI promo ters, whereas in HCT-116 cells, butyrate upregulates expression of these pr omoters. 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 induct ion by butyrate of Tcf-repressible promoters in these cells. These findings indicate that sodium butyrate modulates the Wnt pathway in SW620 and HCT-1 16 cells in a different manner and that these differences have consequences for promoter activity that may influence the physiologic response to butyr ate. (C) 2002 Wiley-Liss, Inc.