CYP2E1-dependent upregulation of SIRT7 is response to alcohol mediated metastasis in hepatocellular carcinoma.
CYP2E1-dependent upregulation of SIRT7 is response to alcohol mediated metastasis in hepatocellular carcinoma.
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DOI：
10.1038/s41417-022-00512-y
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发表时间：
2022-07
影响因子：
6.4
通讯作者：
Chen Zhang;Jinqiu Zhao;Jie Zhao;Bo Liu;W. Tang;Yi Liu;Wenxiang Huang;S. Weinman;Zhuan Li
中科院分区：
文献类型：
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作者：
Chen Zhang;Jinqiu Zhao;Jie Zhao;Bo Liu;W. Tang;Yi Liu;Wenxiang Huang;S. Weinman;Zhuan Li
长期饮酒是确定的肝癌发生和转移的危险因素。与酒精相关的肿瘤发生的多种机制已被提出，包括有毒反应性代谢物的产生、氧化应激和脂肪积累。然而，酒精介导的肝癌转移的潜在机制在很大程度上仍不清楚。我们先前已经证明，SIRT7通过改变人肝细胞癌中依赖于P53的途径来调节化疗敏感性。在目前的研究中，我们进一步揭示了SIRT7是促进肝癌转移的关键因素。SIRT7的表达与疾病分期有关，高SIRT7预示着较差的总体和无病生存率。SIRT7过表达促进肝癌细胞迁移和EMT，而SIRT7过表达则相反。机制上，我们发现SIRT7通过FOXO_3依赖的启动子结合和H3K18去乙酰化来抑制E-钙粘附素的表达。敲除FOXO_3可阻断SIRT7对E-钙粘蛋白转录的抑制作用。更重要的是，我们在体外和体内都发现酒精处理上调了肝细胞SIRT7，抑制了E-钙粘附素的表达，其途径是通过细胞色素P450 2E/ROS轴。在原代肝细胞或酒精喂养的−/−小鼠中，抗氧化剂处理削弱了这些影响。降低SIRT7活性可完全阻断酒精对体内肝癌转移的促进作用。综上所述，我们的数据显示SIRT7是酒精介导的肝细胞癌转移的关键调节因子。
Long-term alcohol use is a confirmed risk factor of liver cancer tumorigenesis and metastasis. Multiple mechanisms responsible for alcohol related tumorigenesis have been proposed, including toxic reactive metabolite production, oxidative stress and fat accumulation. However, mechanisms underlying alcohol-mediated liver cancer metastasis remain largely unknown. We have previously demonstrated that SIRT7 regulates chemosensitivity by altering a p53-dependent pathway in human HCC. In the current study, we further revealed that SIRT7 is a critical factor in promoting liver cancer metastasis. SIRT7 expression is associated with disease stage and high SIRT7 predicts worse overall and disease-free survival. Overexpression of SIRT7 promotes HCC cell migration and EMT while knockdown of SIRT7 showed opposite effects. Mechanistically, we found that SIRT7 suppresses E-Cadherin expression through FOXO3-dependent promoter binding and H3K18 deacetylation. Knockdown of FOXO3 abolished the suppressive effect of SIRT7 on E-cadherin transcription. More importantly, we identified that alcohol treatment upregulates SIRT7 and suppresses E-cadherin expression via a CYP2E/ROS axis in hepatocytes both in vitro and in vivo. Antioxidant treatment in primary hepatocyte or CYP2E1−/−mice fed with alcohol impaired those effects. Reducing SIRT7 activity completely abolished alcohol-mediated promotion of liver cancer metastasis in vivo. Taken together, our data reveal that SIRT7 is a pivotal regulator of alcohol-mediated HCC metastasis.