Deficiency of Histone Methyltransferase SET Domain-Containing 2 in Liver Leads to Abnormal Lipid Metabolism and HCC
Deficiency of Histone Methyltransferase SET Domain-Containing 2 in Liver Leads to Abnormal Lipid Metabolism and HCC
复制标题
肝脏中组蛋白甲基转移酶 SET 结构域 2 的缺乏导致脂质代谢异常和肝癌
DOI：
10.1002/hep.31594
复制
发表时间：
2021-03-17
期刊：
影响因子：
13.5
通讯作者：
Wu, Min
中科院分区：
文献类型：
--
作者：
Li, Xue-Jing;Li, Qing-Lan;Wu, Min
组蛋白甲基转移酶SET结构域2（SET domain containing 2，SET D2）催化的组蛋白3（histone 3，H3 K36 me 3）上Lys 36的三甲基化是从酵母到哺乳动物最保守的表观遗传标记之一。SETD 2经常在多种癌症中发生突变，并作为肿瘤抑制因子。方法和结果在这里，使用肝脏特异性Setd 2耗竭模型，我们发现Setd 2缺乏足以引发自发性HCC。同时，Setd 2耗竭显著增加了二乙基亚硝胺诱导的HCC模型的肿瘤和肿瘤大小。机制研究表明，Setd 2不仅通过调节DNA损伤反应，而且还通过调节肝脏脂质代谢来抑制HCC。Setd 2缺陷下调H3 K36 me 3富集和胆固醇流出基因的表达，并引起脂质蓄积。高脂饮食增加了Setd 2基因缺陷小鼠体内的脂质蓄积，促进了肝癌的发生。染色质免疫沉淀测序分析进一步揭示Setd 2缺失诱导肝脏中c-Jun/激活蛋白1（AP-1）活化，其被积累的脂质所抑制。结论Setd 2在肝癌中的作用及其调节胆固醇稳态和c-Jun/AP-1信号通路的可能机制已被揭示。
Background and Aims Trimethylation of Lys36 on histone 3 (H3K36me3) catalyzed by histone methyltransferase SET domain-containing 2 (SETD2) is one of the most conserved epigenetic marks from yeast to mammals. SETD2 is frequently mutated in multiple cancers and acts as a tumor suppressor.Approach and Results Here, using a liver-specific Setd2 depletion model, we found that Setd2 deficiency is sufficient to trigger spontaneous HCC. Meanwhile, Setd2 depletion significantly increased tumor and tumor size of a diethylnitrosamine-induced HCC model. The mechanistic study showed that Setd2 suppresses HCC not only through modulating DNA damage response, but also by regulating lipid metabolism in the liver. Setd2 deficiency down-regulated H3K36me3 enrichment and expression of cholesterol efflux genes and caused lipid accumulation. High-fat diet enhanced lipid accumulation and promoted the development of HCC in Setd2-deficient mice. Chromatin immunoprecipitation sequencing analysis further revealed that Setd2 depletion induced c-Jun/activator protein 1 (AP-1) activation in the liver, which was trigged by accumulated lipid. c-Jun acts as an oncogene in HCC and functions through inhibiting p53 in Setd2-deficient cells.Conclusions We revealed the roles of Setd2 in HCC and the underlying mechanisms in regulating cholesterol homeostasis and c-Jun/AP-1 signaling.