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USP22 regulates lipidome accumulation by stabilizing PPARγ in hepatocellular carcinoma

Author

Listed:
  • Zhen Ning

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences
    The First Affiliated Hospital of Dalian Medical University, Dalian Medical University
    Liaoning Key Laboratory of Molecular Targeted Drugs in Hepatobiliary and Pancreatic Cancer)

  • Xin Guo

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences
    The First Affiliated Hospital of Dalian Medical University, Dalian Medical University)

  • Xiaolong Liu

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Chang Lu

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences
    The First Affiliated Hospital of Dalian Medical University, Dalian Medical University)

  • Aman Wang

    (The First Affiliated Hospital of Dalian Medical University, Dalian Medical University
    Liaoning Key Laboratory of Molecular Targeted Drugs in Hepatobiliary and Pancreatic Cancer)

  • Xiaolin Wang

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Wen Wang

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Huan Chen

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Wangshu Qin

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Xinyu Liu

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Lina Zhou

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Chi Ma

    (The First Affiliated Hospital of Dalian Medical University, Dalian Medical University
    Liaoning Key Laboratory of Molecular Targeted Drugs in Hepatobiliary and Pancreatic Cancer)

  • Jian Du

    (The First Affiliated Hospital of Dalian Medical University, Dalian Medical University
    Liaoning Key Laboratory of Molecular Targeted Drugs in Hepatobiliary and Pancreatic Cancer)

  • Zhikun Lin

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences
    The First Affiliated Hospital of Dalian Medical University, Dalian Medical University
    Liaoning Key Laboratory of Molecular Targeted Drugs in Hepatobiliary and Pancreatic Cancer)

  • Haifeng Luo

    (The First Affiliated Hospital of Dalian Medical University, Dalian Medical University
    Liaoning Key Laboratory of Molecular Targeted Drugs in Hepatobiliary and Pancreatic Cancer)

  • Wuxiyar Otkur

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Huan Qi

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Di Chen

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Tian Xia

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Jiwei Liu

    (The First Affiliated Hospital of Dalian Medical University, Dalian Medical University
    Liaoning Key Laboratory of Molecular Targeted Drugs in Hepatobiliary and Pancreatic Cancer)

  • Guang Tan

    (The First Affiliated Hospital of Dalian Medical University, Dalian Medical University
    Liaoning Key Laboratory of Molecular Targeted Drugs in Hepatobiliary and Pancreatic Cancer)

  • Guowang Xu

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences)

  • Hai-long Piao

    (Dalian Institute of Chemical Physics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    China Medical University)

Abstract

Elevated de novo lipogenesis is considered to be a crucial factor in hepatocellular carcinoma (HCC) development. Herein, we identify ubiquitin-specific protease 22 (USP22) as a key regulator for de novo fatty acid synthesis, which directly interacts with deubiquitinates and stabilizes peroxisome proliferator-activated receptor gamma (PPARγ) through K48-linked deubiquitination, and in turn, this stabilization increases acetyl-CoA carboxylase (ACC) and ATP citrate lyase (ACLY) expressions. In addition, we find that USP22 promotes de novo fatty acid synthesis and contributes to HCC tumorigenesis, however, this tumorigenicity is suppressed by inhibiting the expression of PPARγ, ACLY, or ACC in in vivo tumorigenesis experiments. In HCC, high expression of USP22 positively correlates with PPARγ, ACLY or ACC expression, and associates with a poor prognosis. Taken together, we identify a USP22-regulated lipogenesis mechanism that involves the PPARγ-ACLY/ACC axis in HCC tumorigenesis and provide a rationale for therapeutic targeting of lipogenesis via USP22 inhibition.

Suggested Citation

  • Zhen Ning & Xin Guo & Xiaolong Liu & Chang Lu & Aman Wang & Xiaolin Wang & Wen Wang & Huan Chen & Wangshu Qin & Xinyu Liu & Lina Zhou & Chi Ma & Jian Du & Zhikun Lin & Haifeng Luo & Wuxiyar Otkur & Hu, 2022. "USP22 regulates lipidome accumulation by stabilizing PPARγ in hepatocellular carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29846-9
    DOI: 10.1038/s41467-022-29846-9
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    References listed on IDEAS

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    1. Bin Liu & Shangwen Jiang & Min Li & Xuelian Xiong & Mingrui Zhu & Duanzhuo Li & Lei Zhao & Lili Qian & Linhui Zhai & Jing Li & Han Lu & Shengnan Sun & Jiandie Lin & Yan Lu & Xiaoying Li & Minjia Tan, 2018. "Proteome-wide analysis of USP14 substrates revealed its role in hepatosteatosis via stabilization of FASN," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    2. Ganna Panasyuk & Catherine Espeillac & Céline Chauvin & Ludivine A. Pradelli & Yasuo Horie & Akira Suzuki & Jean-Sebastien Annicotte & Lluis Fajas & Marc Foretz & Francisco Verdeguer & Marco Pontoglio, 2012. "PPARγ contributes to PKM2 and HK2 expression in fatty liver," Nature Communications, Nature, vol. 3(1), pages 1-9, January.
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