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The [Beta]-catenin signaling pathway is designated in nearly all colon cancers. Nonhypercalcemic vitamin D3 (1[Alpha], 25-dehydroxyvitamin [D.sub.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).sub.2][D.sub.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.sub.2])[D.sub.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).sub.2][D.sub.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 1[Alpha], 25[(OH).sub.2][D.sub.3] 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.