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PARG inhibition limits HCC progression and potentiates the efficacy of immune checkpoint therapy

  • Author Footnotes
    † These authors have contributed equally to this work and share first authorship.
    Mincheng Yu
    Footnotes
    † These authors have contributed equally to this work and share first authorship.
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Author Footnotes
    † These authors have contributed equally to this work and share first authorship.
    Zheng Chen
    Footnotes
    † These authors have contributed equally to this work and share first authorship.
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Author Footnotes
    † These authors have contributed equally to this work and share first authorship.
    Qiang Zhou
    Footnotes
    † These authors have contributed equally to this work and share first authorship.
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Author Footnotes
    † These authors have contributed equally to this work and share first authorship.
    Bo Zhang
    Footnotes
    † These authors have contributed equally to this work and share first authorship.
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Author Footnotes
    † These authors have contributed equally to this work and share first authorship.
    Jinlong Huang
    Footnotes
    † These authors have contributed equally to this work and share first authorship.
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Lei Jin
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Binghai Zhou
    Affiliations
    Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, P.R. China
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  • Shuang Liu
    Affiliations
    Neurosurgery Department of Zhongshan Hospital, Fudan University, Shanghai, 200032, P.R. China
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  • Jiuliang Yan
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Xiaoqiang Li
    Affiliations
    Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen, 51800, P.R. China
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  • Wentao Zhang
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Chunxiao Liu
    Affiliations
    Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
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  • Bo Hu
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Peiyao Fu
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Chenhao Zhou
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Yongfeng Xu
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Yongsheng Xiao
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Jian Zhou
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Jia Fan
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Ning Ren
    Correspondence
    Corresponding authors. Address: Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R, China.
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China

    Institute of Fudan Minhang Academic Health System, Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, Shanghai, 201199, P.R. China
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  • Mien-Chie Hung
    Correspondence
    Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan.
    Affiliations
    Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan
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  • Lei Guo
    Correspondence
    Corresponding authors. Address: Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R, China.
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
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  • Hui Li
    Correspondence
    Corresponding authors. Address: Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R, China.
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China

    Shanghai Medical College and Zhongshan Hospital Immunotherapy Technology Transfer Center, Shanghai, 200031, P.R. China
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  • Qinghai Ye
    Correspondence
    Corresponding authors. Address: Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R, China.
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P.R. China
    Search for articles by this author
  • Author Footnotes
    † These authors have contributed equally to this work and share first authorship.
Published:February 11, 2022DOI:https://doi.org/10.1016/j.jhep.2022.01.026

      Highlights

      • PARG is upregulated in HCC tissues and predicts poor prognosis.
      • PARG regulation of c-MYC expression is dependent on PARG-mediated DDB1 degradation in HCC.
      • PARG promotes growth and metastasis of HCC via a newly identified PARG/DDB1/c-Myc signaling axis.
      • PARG promotes MMR expression and could potentially be used to predict which patients might benefit from anti-PD-1 treatment.
      • PARG inhibition potentiates the efficacy of PD-1 blockade in a murine HCC model.

      Background & Aims

      Although the treatment of hepatocellular carcinoma (HCC) has been revolutionized by the advent of effective systemic therapies, the prognosis of patients with HCC remains dismal. Herein, we examined the pathophysiological role of PARG and assessed the utility of targeting dePARylation for HCC therapy.

      Methods

      The oncogenic function of PARG was evaluated in 2 orthotopic xenograft models and a Pargflox/flox mice model. The therapeutic efficacy of PARG inhibitors in combination with an anti-PD-1 antibody were assessed in murine orthotopic models. Microarray analysis was used to evaluate the pathological relevance of the PARG/DDB1/c-Myc/MMR axis.

      Results

      High PARG expression was strongly associated with poor HCC prognosis. Hepatocyte-specific PARG deletion significantly impaired liver tumorigenesis. PARG promoted HCC growth and metastasis through DDB1-dependent modulation of c-Myc. Specifically, PARG dePARylated DDB1 and consequently promoted DDB1 autoubiquitination, thus stabilizing the c-Myc protein in HCC cells. PARG downregulation attenuated c-Myc-induced MMR expression and PARG deficiency was correlated with a favorable prognosis in patients with HCC treated with anti-PD-1-based immunotherapy. In addition, PARG inhibitors could act in synergy with anti-PD-1 antibodies in orthotopic mouse models.

      Conclusions

      PARG can act as an oncogene in HCC by modulating PARG/DDB1/c-Myc signaling and could be used as a biomarker to identify patients with HCC who may benefit from anti-PD-1 treatment. Our findings suggest that co-inhibition of PARG and PD-1 is an effective novel combination strategy for patients with HCC.

      Lay summary

      The increase in deaths due to hepatocellular carcinoma (HCC) is a growing concern, with the mechanisms responsible for HCC development still incompletely understood. Herein, we identify a novel mechanism by which the protein PARG contributes to HCC development. Inhibition of PARG increased the efficacy of anti-PD-1 therapy (a type of immunotherapy) in HCC. These findings support the future clinical development of PARG inhibitors, potentially in combination with anti-PD-1 inhibitors.

      Graphical abstract

      Keywords

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