Aibara Daisuke
Faculty of Pharmaceutical Science, Fukuoka University.
Yakugaku Zasshi. 2024;144(2):157-161. doi: 10.1248/yakushi.23-00176.
Chronic activation of the nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARA), causes hepatocellular proliferation and increases the incidence of hepatocellular carcinoma in rodents. However, the molecular mechanisms underlying hepatocyte proliferation by activated PPARA remain ambiguous. This review focuses on the genes repressed by PPARA and describes the mechanism by which it promotes hepatocyte proliferation in mice. PPARA undergoes autoinduction, leading to its overexpression by an agonist. PPARA subsequently activates the E2F transcription factor 8 (E2f8), which then activates the ubiquitin-like protein containing the PHD and RING finger domains 1 (Uhrf1). UHRF1, in complex with histone deacetylase 1 and DNA methyltransferase 1, stimulates DNA methylation and recruitment of histone H3 containing trimethylated lysine 9 to the promoters of specific target genes, including E-cadherin/cadherin 1 (Cdh1), resulting in their downregulation. Decreased expression of CDH1 stimulates Wnt signaling, upregulation of oncogenes, including Myc and the cell cycle control genes, cyclin D1 and Jun, and enhances hepatocyte hyperproliferation. Therefore, the PPARA-E2F8-UHRF1-CDH1-Wnt signaling axis is involved in the epigenetic regulation of hepatocyte proliferation. This review provides insights into the mechanisms underlying hepatocarcinogenesis induced by non-genotoxic substances.
核受体过氧化物酶体增殖物激活受体α（PPARA）的慢性激活会导致肝细胞增殖，并增加啮齿动物肝细胞癌的发病率。然而，激活的PPARA促进肝细胞增殖的分子机制仍不明确。本综述聚焦于受PPARA抑制的基因，并描述其在小鼠中促进肝细胞增殖的机制。PPARA会发生自身诱导，导致其被激动剂过度表达。PPARA随后激活E2F转录因子8（E2f8），E2f8进而激活含PHD和RING指结构域1的泛素样蛋白（Uhrf1）。UHRF1与组蛋白去乙酰化酶1和DNA甲基转移酶1形成复合物，刺激DNA甲基化，并将含有三甲基化赖氨酸9的组蛋白H3招募至特定靶基因（包括E-钙黏蛋白/钙黏蛋白1，即Cdh1）的启动子区域，导致这些基因下调。CDH1表达降低会刺激Wnt信号通路，上调包括Myc、细胞周期调控基因细胞周期蛋白D1和Jun在内的癌基因，并增强肝细胞过度增殖。因此，PPARA-E2F8-UHRF1-CDH1-Wnt信号轴参与了肝细胞增殖的表观遗传调控。本综述为非遗传毒性物质诱导肝癌发生的机制提供了见解。
