Intestinal-specific Hdac3 deletion increases susceptibility to colitis and small intestinal tumour development in mice fed a high fat diet.

Abstract

High fat diets, and inflammation are risk factors for colon cancer, however the underlying mechanisms remain to be fully elucidated. The transcriptional co-repressor HDAC3 has recently emerged as a key regulator of intestinal epithelial responses to diet and inflammation with intestinal-specific Hdac3 deletion (Hdac3IKO) in mice increasing lipid oxidation genes and the rate of lipid oxidation in enterocytes. Hdac3IKO mice are also predisposed to experimentally induced colitis, however whether this is driven by the intestinal metabolic reprogramming, and whether this predisposes these mice to intestinal tumourigenesis is unknown. Herein, we examined the effects of intestinal-specific Hdac3 deletion on colitis-associated intestinal tumourigenesis in mice fed a standard (STD) or HF diet (HFD). Hdac3IKO mice were highly prone to experimentally induced colitis, which was further enhanced by a HFD. Hdac3deletion also accelerated intestinal tumour development, specifically when fed a HFD and most notably in the small intestine where lipid absorption is maximal. Expression of proteins involved in fatty acid metabolism and oxidation (SCD1, EHHADH) were elevated in the small intestine of Hdac3IKO mice fed a HFD, and these mice displayed increased levels of lipid peroxidation, DNA damage, and apoptosis in their villi, as well as extensive expansion of the stem cell and progenitor cell compartment. These findings reveal a novel role for Hdac3 in suppressing colitis and intestinal tumorigenesis, particularly in the context of consumption of a HFD, and reveal a potential mechanism by which HFDs may increase intestinal tumorigenesis by increasing lipid oxidation, DNA damage and intestinal epithelial cell turnover.