Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kobe University, Hyogo, Japan.
Sci Rep. 2020 Dec 4;10(1):21268. doi: 10.1038/s41598-020-78151-2.
Most hepatocellular carcinomas (HCCs) develop on the basis of chronic hepatitis, but the mechanism of epigenetic regulation in inflammatory hepatocarcinogenesis has yet to be elucidated. Among de novo DNA methyltransferases (DNMTs), DNMT3B has lately been reported to act specifically on actively transcribed genes, suggesting the possibility that it plays a role in the pathogenesis of cancer. We confirmed that DNMT3B isoforms lacking its catalytic domain were highly expressed in HCCs compared with non-tumorous liver tissue. To elucidate the role of DNMT3B in hepatocarcinogenesis, we generated a genetically engineered mouse model with hepatocyte-specific Dnmt3b deletion. The liver of the Dnmt3b-deficient mice exhibited an exacerbation of thioacetamide-induced hepatitis, progression of liver fibrosis and a higher incidence of HCC compared with the liver of the control mice. Whole-genome bisulfite sequencing verified a lower CG methylation level in the Dnmt3b-deficient liver, demonstrating differentially methylated regions throughout the genome. Transcriptome analysis revealed decreased expression of genes related to oxidative phosphorylation in the Dnmt3b-deficient liver. Moreover, primary hepatocytes isolated from the Dnmt3b-deficient mice showed reduced mitochondrial respiratory capacity, leading to the enhancement of oxidative stress in the liver tissue. Our findings suggest the protective role of DNMT3B against chronic inflammation and HCC development via maintaining mitochondrial homeostasis.
大多数肝细胞癌 (HCC) 是在慢性肝炎的基础上发展而来的，但炎症性肝癌发生中的表观遗传调控机制尚不清楚。在从头合成的 DNA 甲基转移酶 (DNMTs) 中，DNMT3B 最近被报道特异性作用于活跃转录的基因，这表明它可能在癌症的发病机制中发挥作用。我们证实，与非肿瘤性肝组织相比，缺乏催化结构域的 DNMT3B 同工型在 HCC 中高度表达。为了阐明 DNMT3B 在肝癌发生中的作用，我们生成了一种具有肝细胞特异性 Dnmt3b 缺失的基因工程小鼠模型。与对照小鼠相比，Dnmt3b 缺陷小鼠的肝脏表现出硫代乙酰胺诱导的肝炎加重、肝纤维化进展和 HCC 发生率更高。全基因组亚硫酸氢盐测序证实 Dnmt3b 缺陷肝脏中的 CG 甲基化水平较低，表明整个基因组存在差异甲基化区域。转录组分析显示，Dnmt3b 缺陷肝脏中与氧化磷酸化相关的基因表达下调。此外，从 Dnmt3b 缺陷小鼠分离的原代肝细胞显示线粒体呼吸能力降低，导致肝组织氧化应激增强。我们的研究结果表明，DNMT3B 通过维持线粒体稳态，对慢性炎症和 HCC 发展起到保护作用。
