Butyrate regulates E-cadherin transcription, isoform expression and intracellular position in colon cancer cells.
Cell-to-cell adhesion, an important event in differentiation, is impaired during advanced stages of tumorigenesis. In this study, we examined the possible regulation of cell-adhesion proteins by the differentiation agent butyrate in LS174T and HM7 cells, two types of human colon cancer cells that differ in their ability to produce mucin and colonize the liver of experimental animals. The more aggressive, high-mucin-producing cell line (HM7), a clone selected from LS174T cells, showed a scattered and undifferentiated ultramorphological appearance and low basal alkaline phosphatase activity; the proteins beta-catenin and E-cadherin, as detected by immunostaining, were expressed in the cells' nuclei. All of these properties were significantly less pronounced in the less aggressive, low-mucin-producing LS174T cells. In both cell lines, butyrate treatment enhanced cell-to-cell interaction, alkaline phosphate activity, translocation of beta-catenin and E-cadherin from the nuclei to the membrane junctions, and transcription and translation of the 120-kDa E-cadherin isoform, but not of its 100-kDa isoform. Analysis of possible mechanisms of E-cadherin up-regulation revealed that butyrate induces the release of nuclear proteins from the E-cadherin promoter sequence, reducing transcription repression. We suggest that butyrate activates E-cadherin transcription through translocation of nuclear transcription factors bearing specific repressor activity. We surmise that abrogation of nuclear 100-kDa E-cadherin and beta-catenin expression following butyrate treatment is related to the control of E-cadherin gene transcription.
Barshishat
M
M
Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot, Israel.
Polak-Charcon
S
S
Schwartz
B
B
D000469:Alkaline Phosphatase / Q000378:metabolism; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D008854:Microscopy, Electron; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation; D051176:beta Catenin
D002087:Butyrates; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D000469:Alkaline Phosphatase