Dietary fish oil and butyrate increase apoptosis and decrease aberrant crypt foci in colon cancer by enhancing histone acetylation and p21waf1/cip1 expression

Abstract

We have previously shown that dietary fish oil and fiber, particularly the highly-fermentable pectin, are protective against colon cancer in a rat model of carcinogenesis. Therefore, based upon the current body of literature and our previous experimental findings, we hypothesized that one mechanism by which dietary fish oil+pectin suppress the promotion stage of colon cancer is through butyrate, the fermentation product of fiber, targeting (in particular) the p21Waf1/Cip1 gene and, via targeted histone hyperacetylation, inducing its expression. We found that dietary butyrate supplementation increased the concentration of fecal butyrate (mole %) in the distal colon, and that this increase corresponded to an increase in histone H4 acetylation. Similarly, diets supplemented with butyrate increased p21Waf1/Cip1 expression despite azoxymethane (AOM) treatment, which was not seen in non-butyrate supplemented diets. Furthermore, fish oil+butyrate diets resulted in the highest levels of apoptosis and the lowest levels of ACF, while corn oil+butyrate diets resulted in the lowest levels of apoptosis and the highest levels of ACF. Thus, it appears that the protective effect of fish oil+butyrate is due to the unique properties of fish oil, providing an environment in which butyrate’s enhancement of histone acetylation and p21 expression are pro-apoptotic, thereby diminishing pre-neoplastic ACF development.