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 d uring advanced stages of tumorigenesis. In this study, we examined the poss ible regulation of cell-adhesion proteins by the differentiation agent buty rate in LS174T and HM7 cells, two types of human colon cancer cells that di ffer in their ability to produce mucin and colonize the liver of experiment al animals. The more aggressive, high-mucin-producing cell line (HM7), a cl one selected from LS174T cells, showed a scattered and undifferentiated ult ramorphological 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. I n both cell lines, butyrate treatment enhanced cell-to-cell interaction, al kaline phosphate activity, translocation of beta-catenin and E-cadherin fro m the nuclei to the membrane junctions, and transcription and translation o f 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 i nduces the release of nuclear proteins from the E-cadherin promoter sequenc e, reducing transcription repression. We suggest that butyrate activates E- cadherin transcription through translocation of nuclear transcription facto rs bearing specific repressor activity. We surmise that abrogation of nucle ar 100-kDa E-cadherin and beta-catenin expression following butyrate treatm ent is related to the control of E-cadherin gene transcription. (C) 2000 Ca ncer Research Campaign.