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CYP2E1-dependent upregulation of SIRT7 is response to alcohol mediated metastasis in hepatocellular carcinoma

Abstract

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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Fig. 1: Elevated SIRT7 expression in human HCC and associated with poor prognosis.
Fig. 2: SIRT7 promotes HCC metastasis.
Fig. 3: SIRT7 regulates EMT of HCC cells.
Fig. 4: SIRT7 induces H3K18 deacetylation and suppresses E-cadherin via FOXO3.
Fig. 5: EtOH upregulates SIRT7 expression.
Fig. 6: CYP2E1-dependent oxidative stress is responsible for alcohol mediated SIRT7 induction.
Fig. 7: Knockdown SIRT7 prevents alcohol mediated HCC metastasis.

Data availability

All data are within the manuscript and supporting information. Any additional information or data is available upon request.

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Acknowledgements

This study was supported by grant 81974458, 82170607 from the National Natural Science Foundation of China, grant 2021JJ30463 from Hunan Provincial Natural Science Foundation of China, grant 2019RS1042, 2018RS3072, 2019TP1035 from the China Hunan Provincial Science/Technology Department, grant P30 GM118247 from the National Institute of General Medical Sciences from the National Institutes of Health (USA), grants 2022XKQ0205, KF2022001 and a startup grant from Hunan Normal University, and grants AA026025 and AA012863 to SAW from the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (USA). JQZ was supported by grant CSTC2020JCYJ-MSXMX0224 from Chongqing Natural Science Foundation. The specimens used in this study were provided, in part, by the University of Kansas Liver Center Biorepository. The authors acknowledge Dr Laura Nagy (Cleveland Clinic) who provided key materials for this study.

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ZL, CZ, and JQZ performed experiments and acquired data. BHL, WBT, YL, and WXH collected clinical samples. BHL performed the statistical analysis. ZL and SW conducted the experiments, analyzed data, and wrote the paper. All authors edited and approved the final manuscript.

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Correspondence to Zhuan Li.

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All animal handling procedures were approved by the Institutional Animal Care and Use. Committee at The University of Kansas Medical Center. Liver specimens were obtained from the University of Kansas Medical Center, the First Affiliated Hospital of Chongqing Medical University, and the Affiliated Hospital of Hunan Normal University. All studies using human tissue samples were approved by the Human Subjects Committee of the University of Kansas Medical Center. Written informed consent was obtained from all patients and all studies using human tissue samples were approved by the Human Subjects Committee of the University of Kansas Medical Center, Chongqing Medical University and Hunan Normal University School of Medicine.

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Zhang, C., Zhao, J., Zhao, J. et al. CYP2E1-dependent upregulation of SIRT7 is response to alcohol mediated metastasis in hepatocellular carcinoma. Cancer Gene Ther (2022). https://doi.org/10.1038/s41417-022-00512-y

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