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.

Aberrant Epigenetic Alteration in Eca9706 Cells Modulated by Nanoliposomal Quercetin Combined with Butyrate Mediated via Epigenetic-NF-κB Signaling

“…The polyphenol quercetin may prevent cardiovascular disease due to its anti-oxidative stress; the healthy male subjects consumed 150 mg/d quercetin for 8 wks intermitted by a three-week washout phase (Pfeuffer, 2013). The cancer chemopreventive experiment on the Wistar rat hepatocarcinogenesis model treated with histone deacetylase inhibitor, tributyrin (butyric prodrug, 2g/kg body wt) daily for 8 wks resulted in lower HDAC activity and Hdac3 and Hdac4 gene expression, and etc (de Corti, 2013). Moreover, Steliou k et al indicate that the histone deacetylase inhibitor butyrate is not only capable to suppress cancer growth, but also to regulate other medical disorders, such as neurological, DOI:http://dx.doi.org/10.7314/APJCP.2014.15.11.4539 Aberrant Epigenetic Alteration in Eca9706 Cells withNanoliposomal Quercetin and Butyrate -Role of Epigenetic-NF-κB hematological and insulin resistant obesity in mouse models.…”

Histone and Non-Histone Targets of Dietary Deacetylase Inhibitors

“…Tributyrin shares p21WAF1 as a common gene target for de-repression in cancer cells 41 . Similar to butyrate, tributyrin has also been shown to acetylate p53 42 , and valproic acid has been shown to acetylate Ku70 in medulloblastoma cells 43 . More recently, it was reported that the ketone body d-β-hydroxybutyrate (βOHB) (IC 50 : 2~5mM) is an endogenous and specific inhibitor of class I HDACs.…”

Transcriptomic responses provide a new mechanistic basis for the chemopreventive effects of folic acid and tributyrin in rat liver carcinogenesis

“…These doses of folic acid and tributyrin were two times lower from those used in previous studies. [9][10][11][12] Rats (n 5 7) in control group were subjected to the "resistant hepatocyte" model of carcinogenesis only ( Fig. 1).…”