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
Menée sur des rats, cette étude montre que l'effet chimiopréventif de la tributyrine (un promédicament dérivé de l'acide butyrique) sur l'hépatocarcinogenèse est lié à l'acétylation de la protéine nucléaire p53 et à l'activation de la voie de signalisation p53 impliquée dans le processus d'apoptose
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 the present 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 (3 g/kg body weight), and rats in experimental group 2 were treated with tributyrin (2 g/kg body weight) daily for eight 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 to 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 up-regulation 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.
http://carcin.oxfordjournals.org/content/early/2013/04/06/carcin.bgt124.abstract