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CYP2E1-dependent upregulation of SIRT7 is response to alcohol mediated metastasis in hepatocellular carcinoma | Cancer Gene Therapy
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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.
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type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha, China
name:The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, and Hunan Normal University School of Medicine, Changsha, China
name:Department of Pharmacy, Hunan Normal University School of Medicine, Changsha, China
name:Department of Infectious Disease, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
name:Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA
name:The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha, China
name:The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, and Hunan Normal University School of Medicine, Changsha, China
name:Department of Pharmacy, Hunan Normal University School of Medicine, Changsha, China
name:The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha, China
name:The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, and Hunan Normal University School of Medicine, Changsha, China
name:Department of Pharmacy, Hunan Normal University School of Medicine, Changsha, China
name:Department of General Surgery, Peopleâs Hospital of Hunan Province and Affiliated Hospital of Hunan Normal University, Changsha, China
name:Department of Infectious Disease, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
name:Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA
name:Liver Center, University of Kansas Medical Center, Kansas City, USA
name:The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha, China
name:The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, and Hunan Normal University School of Medicine, Changsha, China
name:Department of Pharmacy, Hunan Normal University School of Medicine, Changsha, China
name:Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA
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