USP22 regulates lipidome accumulation by stabilizing PPARγ in hepatocellular carcinoma

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, Huan Qi, Di Chen, Tian Xia, Jiwei Liu, Guang Tan (), Guowang Xu () and Hai-long Piao ()
Additional contact information
Zhen Ning: Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Xin Guo: Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Xiaolong Liu: Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Chang Lu: Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Aman Wang: The First Affiliated Hospital of Dalian Medical University, Dalian Medical University
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
Jian Du: The First Affiliated Hospital of Dalian Medical University, Dalian Medical University
Zhikun Lin: Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Haifeng Luo: The First Affiliated Hospital of Dalian Medical University, Dalian Medical University
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
Guang Tan: The First Affiliated Hospital of Dalian Medical University, Dalian Medical University
Guowang Xu: Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Hai-long Piao: Dalian Institute of Chemical Physics, Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29846-9

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