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 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
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DOI：
10.1093/carcin/bgt124
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发表时间：
2013-08-01
期刊：
影响因子：
4.7
通讯作者：
Pogribny, Igor P.
中科院分区：
文献类型：
--
作者：
de Conti, Aline;Tryndyak, Volodymyr;Pogribny, Igor P.
非基因毒性表型改变的可逆性已被探索，以开发新的预防和治疗方法，以控制癌症。此前已有研究表明，组蛋白去乙酰化酶（HDAC）抑制剂三丁酸酯（一种丁酸前药）对大鼠肝癌发生具有化学预防作用。本研究的目的是确定与三丁酸甘油酯化学预防活性相关的分子机制。雄性Wistar大鼠随机分为未处理对照组和2个实验组。实验1组大鼠每日给予麦芽糖糊精（3g/kg体wt），实验2组大鼠每日给予三丁酸甘油酯（2g/kg体wt），连续8周。治疗开始2周后，实验组大鼠建立肝癌发生的耐药肝细胞模型。与实验1组相比，三丁酸甘油酯处理导致HDAC活性降低，Hdac3和Hdac4基因表达降低，组蛋白H3赖氨酸9和18以及组蛋白H4赖氨酸16乙酰化升高。除了组蛋白乙酰化的增加，三丁酸甘油酯引起核p53蛋白乙酰化的增加。这些变化伴随着p53信号网络的正常化，特别是促凋亡基因的上调，随后三丁酸甘油酯处理大鼠肝脏中凋亡和自噬的增加。这些结果表明，三丁酸甘油酯的化学预防活性可能与组蛋白和p53乙酰化的增加有关，从而诱导p53凋亡通路。
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.