title: Molecular pathways: gene-environment interactions regulating dietary fiber induction of proliferation and apoptosis via butyrate for cancer prevention.
abstract: Gene-environment interactions are so numerous and biologically complicated that it can be challenging to understand their role in cancer. However, dietary fiber and colorectal cancer prevention may represent a tractable model system. Fiber is fermented by colonic bacteria into short-chain fatty acids such as butyrate. One molecular pathway that has emerged involves butyrate having differential effects depending on its concentration and the metabolic state of the cell. Low-moderate concentrations, which are present near the base of colonic crypts, are readily metabolized in the mitochondria to stimulate cell proliferation via energetics. Higher concentrations, which are present near the lumen, exceed the metabolic capacity of the colonocyte. Unmetabolized butyrate enters the nucleus and functions as a histone deacetylase (HDAC) inhibitor that epigenetically regulates gene expression to inhibit cell proliferation and induce apoptosis as the colonocytes exfoliate into the lumen. Butyrate may therefore play a role in normal homeostasis by promoting turnover of the colonic epithelium. Because cancerous colonocytes undergo the Warburg effect, their preferred energy source is glucose instead of butyrate. Consequently, even moderate concentrations of butyrate accumulate in cancerous colonocytes and function as HDAC inhibitors to inhibit cell proliferation and induce apoptosis. These findings implicate a bacterial metabolite with metaboloepigenetic properties in tumor suppression.
authors.affiliation: Author's Affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Bultman
mesh_terms: D000818:Animals; D017209:Apoptosis; D002087:Butyrates / Q000378:metabolism*; D049109:Cell Proliferation; D003106:Colon / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000517:prevention & control*; D004043:Dietary Fiber / Q000378:metabolism*; D044127:Epigenesis, Genetic; D059647:Gene-Environment Interaction; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: D002087:Butyrates; D004043:Dietary Fiber; D056572:Histone Deacetylase Inhibitors; D043562:Receptors, G-Protein-Coupled