1,25-Dihydroxycholecalciferol Enhances Butyrate-Induced p21Waf1/Cip1 Expression

Butyrate, a short-chain fatty acid produced in the colon, as well as its prodrug tributyrin, reduce proliferation and increase differentiation of colon cancer cells. p21Waf1/Cip1 and p27Kip1 are negative regulators of cell cycle and are thought to have a key function in the differentiation of various cell lines. We studied the effects of butyrate on differentiation, VDR expression, as well as on p21Waf1/Cip1 and p27Kip1 expression in human colon cancer cells (Caco-2). Butyrate induced cell differentiation, which was further enhanced after addition of 1,25-dihydroxycholecalciferol. Synergistic effect of butyrate and dihydroxycholecalciferol in Caco-2 cells was due to butyrate-induced overexpression of VDR. While butyrate as well as dihydroxycholecalciferol increased p21Waf1/Cip1 and p27Kip1 expression, in contrast combined exposure of butyrate and dihydroxycholecalciferol resulted in a synergistic amplification of p21Waf1/Cip1, but not of p27Kip1 expression. These data imply that butyrate selectively increases p21Waf1/Cip1 expression via upregulation of VDR in Caco-2 cells.