The
short-chain fatty acid butyrate plays an essential role in colonic mucosa homeostasis through the capacity to block the cell cycle, regulate differentiation and to induce apoptosis. The beneficial effect of
dietary fibers on preventing
colon cancer is essentially mediated through
butyrate, derived from
luminal fermentation of fibers by intestinal bacteria. In epithelial cells of the colon, both in normal and
colon cancer cells, the expression of several genes is positively or negatively regulated by
butyrate likely through modulation of
histone acetylation and thereby affecting the transcriptional activity of genes.
Calretinin (CALB2) is a member of the EF-hand family of Ca(2+)-
binding proteins and is expressed in a majority of poorly differentiated colon
carcinoma and additionally in
mesothelioma of the epithelioid and mixed type. Since CALB2 is one of the genes negatively regulated by
butyrate in
colon cancer cells and
butyrate decreases
calretinin protein expression levels in those cells, we investigated whether expression is regulated via putative
butyrate-responsive elements (BRE) in the human CALB2 promoter. We identified two elements that act as
butyrate-sensitive repressors in all
colon cancer cell lines tested (CaCo-2, HT-29, Co-115/3). In contrast, in cells of mesothelial origin, MeT-5A and ZL34, the same two elements do not operate as
butyrate-sensitive repressors and
calretinin expression levels are insensitive to
butyrate indicative of cell type-specific regulation of the CALB2 promoter.
Calretinin expression in
colon cancer cells is negatively regulated by
butyrate via a bipartite BRE flanking the TATA box and this may be linked to
butyrate's chemopreventive activity.