title: The chemopreventive activity of the butyric acid prodrug tributyrin in experimental rat hepatocarcinogenesis is associated with p53 acetylation and activation of the p53 apoptotic signaling pathway.
abstract: The reversibility of non-genotoxic phenotypic alterations has been explored in order to develop novel preventive and therapeutic approaches for cancer control. Previously, it has been demonstrated that histone deacetylase (HDAC) inhibitor tributyrin, a butyric acid prodrug, to have chemopreventive effects on rat hepatocarcinogenesis. The goal of this study was to determine molecular mechanisms associated with the chemopreventive activity of tributyrin. Male Wistar rats were allocated randomly to untreated control group and two experimental groups. Rats in the experimental group 1 were treated with maltodextrin (3g/kg body wt), and rats in experimental group 2 were treated with tributyrin (2g/kg body wt) daily for 8 weeks. Two weeks after treatment initiation, rats from experimental groups were subjected to a 'resistant hepatocyte' model of hepatocarcinogenesis. Treatment with tributyrin resulted in lower HDAC activity and Hdac3 and Hdac4 gene expression, and an increase of histone H3 lysine 9 and 18 and histone H4 lysine 16 acetylation as compared with the experimental group 1. In addition to the increase in histone acetylation, tributyrin caused an increase in the acetylation of the nuclear p53 protein. These changes were accompanied by a normalization of the p53-signaling network, particularly by the upregulation of pro-apoptotic genes, and a consequent increase of apoptosis and autophagy in the livers of tributyrin-treated rats. These results indicate that the chemopreventive activity of tributyrin may be related to an increase of histone and p53 acetylation, which could lead to the induction of the p53 apoptotic pathway.
authors.affiliation: Department of Food and Experimental Nutrition, Laboratory of Diet, Nutrition and Cancer, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Aline
authors.initials: A
authors.lastname: de Conti
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Tryndyak
authors.forename: Igor
authors.initials: I
authors.lastname: Koturbash
authors.forename: Renato
authors.initials: R
authors.lastname: Heidor
authors.forename: Joice
authors.initials: J
authors.lastname: Kuroiwa-Trzmielina
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Ong
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
authors.forename: Fernando S
authors.initials: FS
authors.lastname: Moreno
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D020148:Butyric Acid / Q000494:pharmacology*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008297:Male; D011230:Precancerous Conditions / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011355:Prodrugs / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014280:Triglycerides / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011355:Prodrugs; D014280:Triglycerides; D016159:Tumor Suppressor Protein p53; D020148:Butyric Acid; D006655:Histone Deacetylases; D008239:Lysine; C005830:tributyrin