Epigenetic Mechanisms by Which Chemoprotective Natural Compounds Promote RXR/FXR Signaling and Reduce Colon Cancer Progression

Abstract

Chemoprotective natural compounds include amphiphilic n‐3 polyunsaturated fatty acids (PUFA) found in fish oil, and butyrate, a histone deacetylase inhibitor, generated in the colonic lumen via the fermentation of fiber by gut microbes. Using preclinical models, we have demonstrated that n‐3 PUFA and butyrate synergistically reduce colon tumor development by increasing targeted apoptosis of DNA damaged cells, thus reducing tumorigenesis. Therefore, we assessed epigenetic reprogramming using high‐resolution transcriptome and chromatin state maps from epithelial cells isolated from rats injected with a colon‐specific carcinogen (AOM) and fed a combination of fermentable fiber (butyrate) plus n‐3 PUFA vs control.Colonocyte transcriptional profile analysis (RNA‐Seq and ChIP‐Seq) of n‐3 PUFA/butyrate vs control rats at the cancer progression stage, 10 wks post AOM exposure, revealed 26 differentially expressed genes related to the RXR/FXR signaling (IPA pathway analysis p<0.001). Differential H3K9ac occupancy concurrent with the induced pathway genes included hepatic transport proteins (ABCA1 and ABCA2), metabolizing enzymes (CYP2B6, GSTA3), biosynthesis enzymes (CYP7A1), RXR ligand synthesis (ALDH8), and nuclear hormone receptor (FXR) linked to increased metabolism, transport and biosynthesis of lipid, bile acid and xenobiotics. In conclusion, we propose that the chemoprotective effects of n‐3 PUFA/butyrate combination during cancer progression include activated transcription and chromatin acetylation of RXR/FXR function and lipid metabolism associated genes.