Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of β-catenin signaling

The beta -catenin signaling pathway is deregulated in nearly all colon cancers. Nonhypercalcemic vitamin D3 (1 alpha ,25-dehydroxyvitamin D-3) analogues are candidate drugs to treat this neoplasia. We show that these compounds promote the differentiation of human colon carcinoma SW480 cells expressing vitamin D receptors (VDRs) (SW480-ADH) but not that of a malignant subline (SW480-R) or metastasic derivative (SW620) cells lacking VDR. 1 alpha ,25(OH)(2)D-3 induced the expression of E-cadherin and other adhesion proteins (occludin, Zonula occludens [ZO]-1, ZO-2, vinculin) and promoted the translocation of beta -catenin, plakoglobin, and ZO-1 from the nucleus to the plasma membrane. Ligand-activated VDR competed with T cell transcription factor (TCF)-4 for beta -catenin binding. Accordingly, 1 alpha ,25(OH)(2)D-3 repressed beta -catenin-TCF-4 transcriptional activity. Moreover, VDR activity was enhanced by ectopic beta -catenin and reduced by TCF-4. Also, 1 alpha ,25(OH)(2)D-3 inhibited expression of beta -catenin-TCF-4-responsive genes, c-myc, peroxisome proliferator-activated receptor delta, Tcf-1, and CD44, whereas it induced expression of ZO-1. Our results show that lot,25(OH)2D3 induces E-cadherin and modulates beta -catenin-TCF-4 target genes in a manner opposite to that of beta -catenin, promoting the differentiation of colon carcinoma cells.