Pogribny Igor P, Tryndyak Volodymyr P, Muskhelishvili Levan, Rusyn Ivan, Ross Sharon A
National Center for Toxicological Research, Jefferson, AR 72079, USA.
J Nutr. 2007 Jan;137(1 Suppl):216S-222S. doi: 10.1093/jn/137.1.216S.
The methyl-deficient model of endogenous hepatocarcinogenesis in rodents is unique in that dietary omission rather than the addition of chemical carcinogens leads to tumor formation. Thus, the biochemical and molecular events predisposing to cancer in this model result from chronic metabolic stress and provide an ideal model system to study progressive alterations that occur during carcinogenesis. Moreover, epigenetic alterations imposed by this diet are believed to be 1 of the main mechanisms responsible for malignant transformation of rat liver cells. In this study we examined the changes in global histone modification patterns in liver during hepatocarcinogenesis induced by methyl deficiency. Feeding animals the methyl-deficient diet (MDD) led to progressive loss of histone H4 lysine 20 trimethylation (H4K20me3), H3 lysine 9 trimethylation (H3K9me3), and histone H3 lysine 9 (H3K9ac) and histone H4 lysine 16 (H4K16ac) acetylation. A considerable decrease of H4K20me3 and H3K9ac was also detected in liver tumors induced by MDD. In contrast, liver tumors displayed an increase in H3K9me3 and H4K16ac. To determine the possible mechanism of alterations of histone modifications, we analyzed the expression of histone-modifying enzymes in liver during hepatocarcinogenesis. The expression of Suv4-20h2 and RIZ1 histone methyltransferases (HMTs) steadily decreased along with the development of liver tumors and reached its lowest level in tumor tissue, whereas the expression of Suv39-h1 HMT and histone acetyltransferase 1 (HAT1) substantially increased in tumors. These results illustrate the complexity and importance of histone modification changes in the etiology of hepatocarcinogenesis induced by MDD.
啮齿动物内源性肝癌发生的甲基缺乏模型具有独特性，即通过饮食中去除而非添加化学致癌物导致肿瘤形成。因此，该模型中易患癌症的生化和分子事件源于慢性代谢应激，并为研究致癌过程中发生的渐进性改变提供了理想的模型系统。此外，这种饮食引起的表观遗传改变被认为是大鼠肝细胞恶性转化的主要机制之一。在本研究中，我们检测了甲基缺乏诱导的肝癌发生过程中肝脏整体组蛋白修饰模式的变化。给动物喂食甲基缺乏饮食（MDD）导致组蛋白H4赖氨酸20三甲基化（H4K20me3）、H3赖氨酸9三甲基化（H3K9me3）以及组蛋白H3赖氨酸9（H3K9ac）和组蛋白H4赖氨酸16（H4K16ac）乙酰化逐渐丧失。在MDD诱导的肝肿瘤中也检测到H4K20me3和H3K9ac显著降低。相反，肝肿瘤中H3K9me3和H4K16ac增加。为了确定组蛋白修饰改变的可能机制，我们分析了肝癌发生过程中肝脏中组蛋白修饰酶的表达。随着肝肿瘤的发展，Suv4 - 20h2和RIZ1组蛋白甲基转移酶（HMTs）的表达稳步下降，并在肿瘤组织中达到最低水平，而Suv39 - h1 HMT和组蛋白乙酰转移酶1（HAT1）的表达在肿瘤中显著增加。这些结果说明了组蛋白修饰变化在MDD诱导的肝癌发生病因中的复杂性和重要性。
