Short-chain fatty acids inhibit intestinal trefoil factor gene expression in colon cancer cells

Abstract

Intestinal trefoil factor (ITF) gene expression was detected in five colon cancer cell lines. ITF was synthesized by mucous cells of LIM 1215 and LIM 1863 lines, from which it is secreted constitutively. The ITF mRNA transcript was estimated to be 0.6 kb. In LIM 1215 cells, the expression of ITF was potently and dose-dependently inhibited by short-chain fatty acids (butyrate > propionate > acetate) within 8 h of application. The inhibitory effect of butyrate was ablated by actinomycin D and preceded its effects on differentiation of LIM 1215 cells as indicated by induction of alkaline phosphatase activity and counting of periodic acid-Schiff-positive cells. The human ITF promoter contained an 11-residue consensus sequence with high homology to the butyrate response element of the cyclin D1 gene. Mobility shift assays show specific binding of this response element to nuclear protein extracts of LIM 1215 cells. We conclude that butyrate inhibits ITF expression in colon cancer cells and that this effect may be mediated transcriptionally and independently of its effects on differentiation.

Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor α, in response to deacetylase inhibition by valproic acid and trichostatin A

“…Correspondingly, oestrogen signalling in MDA-MB-231 ERa cells is not compromised by VPA treatment, indicating that the pS2 gene is directly inhibited by VPA and is not dependent on loss of ERa. This is in agreement with the findings that short-chain fatty acids directly inhibit pS2 expression in colon cancer cells (Tran et al, 1998).…”

“…VPA directly induces methylation of the two HpaII sites encompassed by the phased nucleosome (Sewack and Hansen, 1997; Metivier et al, 2003) overlying the TATA box (Figure 7c). The expression of ERa in MDA-MB-231 is under control of the CMV IE promoter, which is activated by deacetylase inhibitors (Tran et al, 1998). Correspondingly, oestrogen signalling in MDA-MB-231 ERa cells is not compromised by VPA treatment, indicating that the pS2 gene is directly inhibited by VPA and is not dependent on loss of ERa.…”

“…The expression levels of selected genes are indicated (Parker et al, 1986), increasing the 5-methylcytosine content in fibroblast cells from 2.9% (control) to 6.8% (20 mM butyrate). Butyrate also directly reduces the expression of the oestrogen responsive genes TFF1 (pS2) (Tran et al, 1998) and cyclin D1 (Lallemand et al, 1996). We evaluated if VPA directly induced promoter shutoff of the subset of promoters whose products are downregulated on inhibition of deacetylase activity.…”

Trefoil peptide expression and goblet cell number in rat intestine: effects of KGF and fasting-refeeding

“…Nutritional status markedly influences gut mucosal growth and function, but surprisingly little is known about the effects of nutritional factors on intestinal goblet cells or their secreted proteins (6,33,42). Little is known regarding the influence of nutrient intake on gut mucosal responses to recombinant growth factors, including KGF (44,48,49).…”

HDACs and HDAC inhibitors in colon cancer

“…113 Notably, SCFAs appear to promote differentiation of colon cancer cells along the absorptive cell lineage, as the induction of absorptive cell markers such as iALP, is accompanied by a simultaneous inhibition of expression of the markers of goblet cell differentiation Muc2 and ITF. 121,122 Induction of alkaline phosphatase and villin is also an indirect effect of butyrate, requiring de novo protein synthesis, and relatively late in onset, 123 suggesting that HDACi-induced differentiation is the manisfestation of significant reprogramming of colon cancer cells to differentiate along the absorptive cell lineage. Mechanistically, the transcription factor, or factors, that drive this reprogramming remain to be determined.…”