Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Cancer Sci. 2010 Apr;101(4):869-75. doi: 10.1111/j.1349-7006.2009.01460.x. Epub 2009 Dec 8.
Peroxisome proliferators (PPs), non-genotoxic rodent carcinogens, cause the induction of the peroxisomal fatty acid beta-oxidation system, including bifunctional enzyme (BE) and 3-ketoacyl-CoA thiolase (TH), in the liver. GST M1 gene is polymorphic in Sprague-Dawley rats, NC- and KS-type. The KS-type rats showed enhanced susceptibility to ethyl-alpha-chlorophenoxyisobutyrate (clofibrate, CF), one of the PPs. The degree of BE induction was higher in the KS-type and preneoplastic foci developed after 6-8 weeks of treatment, whereas no foci developed in the NC-type. In the preset study, factors involved in different BE inducibility were investigated. There were no differences in hepatic peroxisome proliferator-activated receptor (PPAR) alpha levels between them. Among various coactivators for PPARalpha, only steroid receptor coactivator (SRC)-3 level was higher in the KS-type. To investigate the association between PPARalpha and SRC-3 or other proteins, nuclear extracts from CF-treated livers were applied to a PPARalpha column. In the KS-type, 110, 72, and 42 kDa proteins were bound and these were identified as SRC-3, BE, and TH, respectively. EMSA supported the binding of these proteins to PPARalpha associated to the BE enhancer in CF-treated KS-type, but not in the NC-type. Histone H3 acetylation was increased 11-fold in the KS-type by CF treatment but not in the NC-type. As BE and TH are responsible for acetyl-CoA production and SRC-3 possesses a histone acetyltransferase activity, these results suggest that enhanced BE induction in the KS-type livers is due to acetylation-mediated transcriptional activation and epigenetic mechanisms might be involved in CF-induced rat hepatocarcinogenesis.
过氧化物酶体增殖物（PPs）是非遗传毒性的啮齿动物致癌物质，可诱导肝脏中过氧化物酶体脂肪酸β-氧化系统的诱导，包括双功能酶（BE）和 3-酮酰基辅酶 A 硫解酶（TH）。GST M1 基因在 Sprague-Dawley 大鼠中是多态性的，包括 NC-和 KS-型。KS-型大鼠对乙基-α-氯苯氧异丁酸酯（氯贝酸，CF）等 PPs 的敏感性增强。KS-型大鼠的 BE 诱导程度更高，并且在 6-8 周的治疗后形成了前瘤灶，而 NC-型则没有形成前瘤灶。在本研究中，研究了导致不同 BE 诱导能力的因素。它们之间的肝过氧化物酶体增殖物激活受体（PPAR）α水平没有差异。在各种 PPARα的共激活因子中，KS-型大鼠中的类固醇受体共激活因子（SRC）-3 水平更高。为了研究 PPARα与 SRC-3 或其他蛋白质之间的关联，将 CF 处理后的肝脏核提取物应用于 PPARα柱。在 KS-型中，有 110、72 和 42 kDa 的蛋白质结合，分别鉴定为 SRC-3、BE 和 TH。EMSA 支持 CF 处理的 KS-型中这些蛋白质与与 BE 增强子结合的 PPARα的结合，但在 NC-型中则没有。CF 处理后，KS-型中的组蛋白 H3 乙酰化增加了 11 倍，但 NC-型则没有。由于 BE 和 TH 负责乙酰辅酶 A 的产生，而 SRC-3 具有组蛋白乙酰转移酶活性，因此这些结果表明，KS-型肝脏中 BE 的诱导增强归因于乙酰化介导的转录激活，并且表观遗传机制可能参与了 CF 诱导的大鼠肝癌发生。
