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.

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.

[1]  Tao Zhang,et al.  Autophagy is a cell self-protective mechanism against arsenic-induced cell transformation. , 2012, Toxicological sciences : an official journal of the Society of Toxicology.

[2]  Carine Maenhaut,et al.  Hallmarks of cancer: of all cancer cells, all the time? , 2012, Trends in molecular medicine.

[3]  Jing-Gung Chung,et al.  Allicin induces p53-mediated autophagy in Hep G2 human liver cancer cells. , 2012, Journal of agricultural and food chemistry.

[4]  A. Camargo,et al.  Chemopreventive effects of the dietary histone deacetylase inhibitor tributyrin alone or in combination with vitamin A during the promotion phase of rat hepatocarcinogenesis. , 2012, The Journal of nutritional biochemistry.

[5]  K. Gupta,et al.  Green tea polyphenols increase p53 transcriptional activity and acetylation by suppressing class I histone deacetylases. , 2012, International journal of oncology.

[6]  Xinjiang Wang,et al.  Mdm2 and MdmX partner to regulate p53 , 2012, FEBS letters.

[7]  M. Noguchi,et al.  Tumorigenesis and Neoplastic Progression Aberrant Stratifin Overexpression Is Regulated by Tumor-Associated CpG Demethylation in Lung Adenocarcinoma , 2016 .

[8]  P. Ward,et al.  Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. , 2012, Cancer cell.

[9]  Fang Wang,et al.  The histone deacetylase 4/SP1/microrna‐200a regulatory network contributes to aberrant histone acetylation in hepatocellular carcinoma , 2011, Hepatology.

[10]  C. Plass,et al.  Cancer chemoprevention by targeting the epigenome. , 2011, Current drug targets.

[11]  H. Sitter,et al.  Clinical significance of histone deacetylases 1, 2, 3, and 7: HDAC2 is an independent predictor of survival in HCC , 2011, Virchows Archiv.

[12]  W. Gu,et al.  The impact of acetylation and deacetylation on the p53 pathway , 2011, Protein & Cell.

[13]  Yaping Shi,et al.  Role of HDAC3 on p53 Expression and Apoptosis in T Cells of Patients with Multiple Sclerosis , 2011, PloS one.

[14]  Haiyang Xie,et al.  Identification of Histone Deacetylase 3 as a Biomarker for Tumor Recurrence Following Liver Transplantation in HBV-Associated Hepatocellular Carcinoma , 2010, PloS one.

[15]  S. Baylin,et al.  Linking cell signaling and the epigenetic machinery , 2010, Nature Biotechnology.

[16]  Tian Yang,et al.  microRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity , 2010, British Journal of Cancer.

[17]  Xiao-Li Chen,et al.  Hepatocellular carcinoma-associated protein markers investigated by MALDI-TOF MS. , 2010, Molecular medicine reports.

[18]  S. Barth,et al.  Autophagy: assays and artifacts , 2010, The Journal of pathology.

[19]  J. Debnath,et al.  Autophagy and tumorigenesis , 2010, FEBS letters.

[20]  E. Morselli,et al.  Autophagy regulation by p53. , 2010, Current opinion in cell biology.

[21]  G. Lozano,et al.  E2F3 Is a Mediator of DNA Damage-Induced Apoptosis , 2009, Molecular and Cellular Biology.

[22]  E. Purgatto,et al.  Chemoprevention of rat hepatocarcinogenesis with histone deacetylase inhibitors: Efficacy of tributyrin, a butyric acid prodrug , 2009, International journal of cancer.

[23]  E. Morselli,et al.  Stimulation of autophagy by the p53 target gene Sestrin2 , 2009, Cell cycle.

[24]  D. Richardson,et al.  Growth arrest and DNA damage-45 alpha (GADD45alpha). , 2009, The international journal of biochemistry & cell biology.

[25]  D. Green,et al.  Cytoplasmic functions of the tumour suppressor p53 , 2009, Nature.

[26]  Thomas D. Schmittgen,et al.  Analyzing real-time PCR data by the comparative CT method , 2008, Nature Protocols.

[27]  S. So,et al.  Small interfering RNA targeting CDC25B inhibits liver tumor growth in vitro and in vivo , 2008, Molecular Cancer.

[28]  Y. Maehara,et al.  Clinical Significance of Histone Deacetylase 1 Expression in Patients with Hepatocellular Carcinoma , 2007, Oncology.

[29]  N. Mizushima,et al.  How to Interpret LC3 Immunoblotting , 2007, Autophagy.

[30]  C. Harris,et al.  TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer , 2007, Oncogene.

[31]  Peter A. Jones,et al.  The Epigenomics of Cancer , 2007, Cell.

[32]  H. Pitot.  Adventures in hepatocarcinogenesis. , 2007, Annual review of pathology.

[33]  M. Pierotti,et al.  MAGE-A tumor antigens target p53 transactivation function through histone deacetylase recruitment and confer resistance to chemotherapeutic agents. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[34]  T. Fujii,et al.  Overexpression of pituitary tumor transforming gene 1 in HCC is associated with angiogenesis and poor prognosis , 2006, Hepatology.

[35]  Y. Jeng,et al.  Overexpression of pituitary tumor-transforming gene-1 in hepatocellular carcinoma. , 2006, Hepato-gastroenterology.

[36]  O. Kovalchuk,et al.  Effect of long-term tamoxifen exposure on genotoxic and epigenetic changes in rat liver: implications for tamoxifen-induced hepatocarcinogenesis. , 2005, Carcinogenesis.

[37]  Reuven Agami,et al.  A large-scale RNAi screen in human cells identifies new components of the p53 pathway , 2004, Nature.

[38]  Govind Bhagat,et al.  Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. , 2003, The Journal of clinical investigation.

[39]  L. Kopelovich,et al.  The epigenome as a target for cancer chemoprevention. , 2003, Journal of the National Cancer Institute.

[40]  Q. Su,et al.  Significance of Hepatic Preneoplasia in Risk Identification and Early Detection of Neoplasia * , 2003, Toxicologic pathology.

[41]  R. Hautmann,et al.  Tributyrin induces differentiation, growth arrest and apoptosis in androgen‐sensitive and androgen‐resistant human prostate cancer cell lines , 2000, International journal of cancer.

[42]  J. Meerman,et al.  Loss of nuclear p53 protein in preneoplastic rat hepatocytes is accompanied by Mdm2 and Bcl‐2 overexpression and by defective response to DNA damage in vivo , 2000, Hepatology.

[43]  H. Hibshoosh,et al.  Induction of autophagy and inhibition of tumorigenesis by beclin 1 , 1999, Nature.

[44]  L. Augenlicht,et al.  Initiation of growth arrest and apoptosis of MCF-7 mammary carcinoma cells by tributyrin, a triglyceride analogue of the short-chain fatty acid butyrate, is associated with mitochondrial activity. , 1999, Cancer research.

[45]  U. Stenius,et al.  Wild-type p53 expression in liver tissue and in enzyme-altered foci: an in vivo investigation on diethylnitrosamine-treated rats. , 1998, Carcinogenesis.

[46]  R. Berger,et al.  Identification of BTG2, an antiproliferative p53–dependent component of the DNA damage cellular response pathway , 1996, Nature Genetics.

[47]  M. A. Hayes,et al.  Alternative methods of selecting rat hepatocellular noduli resistant to 2‐acetylaminofluorene , 1987, International journal of cancer.

[48]  P Bannasch,et al.  Preneoplastic lesions as end points in carcinogenicity testing. I. Hepatic preneoplasia. , 1986, Carcinogenesis.

[49]  M. Roizen,et al.  Hallmarks of Cancer: The Next Generation , 2012 .

[50]  E. Ho,et al.  Dietary manipulation of histone structure and function. , 2010, World review of nutrition and dietetics.

[51]  Michael Karin,et al.  p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling , 2009, Cell.