Histone Deacetylase HDAC8 Promotes Insulin Resistance and β-Catenin Activation in NAFLD-Associated Hepatocellular Carcinoma
Histone Deacetylase HDAC8 Promotes Insulin Resistance and β-Catenin Activation in NAFLD-Associated Hepatocellular Carcinoma
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DOI：
10.1158/0008-5472.can-14-3786
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发表时间：
2015-11-15
期刊：
影响因子：
11.2
通讯作者：
Chan, Henry L. Y.
中科院分区：
文献类型：
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作者：
Tian, Yuan;Wong, Vincent W. S.;Chan, Henry L. Y.
肥胖症日益流行，导致非酒精性脂肪性肝病 (NAFLD) 和更严重的表型非酒精性脂肪性肝炎 (NASH)，同时肝细胞癌 (HCC) 发病率也不断增加。越来越多的证据表明，营养过剩和代谢途径可以通过染色质修饰剂的失调触发 DNA 和组蛋白的修饰，从而导致转录活性异常。然而，NAFLD 中 HCC 发展的表观遗传调控仍不清楚。在这里，我们利用饮食和遗传性肥胖促进的 HCC 模型通过定量表达谱揭示了关键的表观遗传调节因子，并表征了组蛋白脱乙酰酶 HDAC8 在 NAFLD 相关肝癌发生中的致癌活性。 HDAC8 直接被脂肪生成转录因子 SREBP-1 上调，它们在 NASH 和 HCC 的饮食肥胖模型中共表达。慢病毒介导的 HDAC8 体内减弱可逆转胰岛素抵抗并降低 NAFLD 相关的致瘤性。通过遗传和药理学方法调节 HDAC8 可抑制 p53/p21 介导的细胞凋亡和 G2-M 期细胞周期停滞，并刺激 β-连环蛋白依赖性细胞增殖。从机制上讲，HDAC8 与染色质修饰剂 EZH2 发生物理相互作用，通过组蛋白 H4 脱乙酰化和 H3 赖氨酸 27 三甲基化来一致抑制 Wnt 拮抗剂。在人类 NAFLD 相关的 HCC 中，与非肿瘤组织相比，肿瘤中的 SREBP-1、HDAC8、EZH2、H4 脱乙酰化、H3K27me3 和活性 β-catenin 水平均呈正相关。总体而言，我们的研究结果显示了 HDAC8 如何驱动 NAFLD 相关肝癌的发生，为预防或治疗肥胖患者的 HCC 提供了新的表观遗传靶点。 (C) 2015 年 AACR。
The growing epidemic of obesity, which causes nonalcoholic fatty liver disease (NAFLD) and the more severe phenotype nonalcoholic steatohepatitis (NASH), has paralleled the increasing incidence of hepatocellular carcinoma (HCC). Accumulating evidence demonstrates that overnutrition and metabolic pathways can trigger modifications of DNA and histones via deregulation of chromatin modifiers, resulting in aberrant transcriptional activity. However, the epigenetic regulation of HCC development in NAFLD remains obscure. Here, we uncover key epigenetic regulators using both dietary and genetic obesity-promoted HCC models through quantitative expression profiling and characterize the oncogenic activities of histone deacetylase HDAC8 in NAFLD-associated hepatocarcinogenesis. HDAC8 is directly upregulated by the lipogenic transcription factor SREBP-1 where they are coexpressed in dietary obesity models of NASH and HCC. Lentiviral-mediated HDAC8 attenuation in vivo reversed insulin resistance and reduced NAFLD-associated tumorigenicity. HDAC8 modulation by genetic and pharmacologic approaches inhibited p53/p21-mediated apoptosis and G2-M phase cell-cycle arrest and stimulated beta-catenin-dependent cell proliferation. Mechanistically, HDAC8 physically interacted with the chromatin modifier EZH2 to concordantly repress Wnt antagonists via histone H4 deacetylation and H3 lysine 27 trimethylation. In human NAFLD-associated HCC, levels of SREBP-1, HDAC8, EZH2, H4 deacetylation, H3K27me3, and active beta-catenin were all correlated positively in tumors compared with nontumor tissues. Overall, our findings show how HDAC8 drives NAFLD-associated hepatocarcinogenesis, offering a novel epigenetic target to prevent or treat HCC in obese patients. (C) 2015 AACR.