Premium
The IKKβ‐USP30‐ACLY Axis Controls Lipogenesis and Tumorigenesis
Author(s) -
Gu Li,
Zhu Yahui,
Lin Xi,
Lu Bingjun,
Zhou Xinyi,
Zhou Feng,
Zhao Qiu,
Prochownik Edward V.,
Li Youjun
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31249
Subject(s) - lipogenesis , hccs , atp citrate lyase , cancer research , carcinogenesis , hepatocellular carcinoma , chemistry , lyase , lipid metabolism , biology , medicine , biochemistry , cancer , enzyme , citrate synthase
Background and Aims Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death that develops as a consequence of obesity, cirrhosis, and chronic hepatitis. However, the pathways along which these changes occur remain incompletely understood. Approach and Results In this study, we show that the deubiquitinase USP30 is abundant in HCCs that arise in mice maintained on high‐fat diets. IKKβ phosphorylated and stabilized USP30, which promoted USP30 to deubiquitinate ATP citrate lyase (ACLY) and fatty acid synthase (FASN). IKKβ also directly phosphorylated ACLY and facilitated the interaction between USP30 and ACLY and the latter’s deubiquitination. In HCCs arising in DEN/CCl 4 ‐treated mice, USP30 deletion attenuated lipogenesis, inflammation, and tumorigenesis regardless of diet. The combination of ACLY inhibitor and programmed death ligand 1 antibody largely suppressed chemical‐induced hepatocarcinogenesis. The IKKβ‐USP30‐ACLY axis was also found to be up‐regulated in human HCCs. Conclusions This study identifies an IKKβ‐USP30‐ACLY axis that plays an essential and wide‐spread role in tumor metabolism and may be a potential therapeutic target in HCC.