The IKKβ-USP30-ACLY Axis Controls Lipogenesis and Tumorigenesis

被引:84
作者
Gu, Li [1 ,2 ]
Zhu, Yahui [1 ,2 ]
Lin, Xi [1 ,2 ]
Lu, Bingjun [1 ,2 ]
Zhou, Xinyi [1 ,2 ]
Zhou, Feng [3 ,4 ]
Zhao, Qiu [3 ,4 ]
Prochownik, Edward, V [5 ,6 ]
Li, Youjun [1 ,2 ]
机构
[1] Wuhan Univ, Coll Life Sci, Hubei Key Lab Cell Homeostasis, Wuhan 430072, Peoples R China
[2] Wuhan Univ, Frontier Sci Ctr Immunol & Metab, Med Res Inst, Wuhan, Peoples R China
[3] Wuhan Univ, Dept Gastroenterol, Zhongnan Hosp, Sch Med, Wuhan, Hubei, Peoples R China
[4] Hubei Clin Ctr & Key Lab Intestinal & Colorectal, Wuhan, Hubei, Peoples R China
[5] Univ Pittsburgh, Childrens Hosp Pittsburgh, Pittsburgh Liver Res Ctr,UPMC, Dept Microbiol & Mol Genet,Med Ctr,Div Hematol On, Pittsburgh, PA USA
[6] Univ Pittsburgh, Med Ctr, Hillman Canc Ctr, UPMC, Pittsburgh, PA USA
基金
中国博士后科学基金;
关键词
ATP-CITRATE-LYASE; NF-KAPPA-B; PROMOTES TUMORIGENESIS; CANCER; INFLAMMATION; INHIBITION; USP30; ACID; PROLIFERATION; BIOSYNTHESIS;
D O I
10.1002/hep.31249
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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. IKK beta phosphorylated and stabilized USP30, which promoted USP30 to deubiquitinate ATP citrate lyase (ACLY) and fatty acid synthase (FASN). IKK beta also directly phosphorylated ACLY and facilitated the interaction between USP30 and ACLY and the latter's deubiquitination. In HCCs arising in DEN/CCl4-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 IKK beta-USP30-ACLY axis was also found to be up-regulated in human HCCs. Conclusions This study identifies an IKK beta-USP30-ACLY axis that plays an essential and wide-spread role in tumor metabolism and may be a potential therapeutic target in HCC.
引用
收藏
页码:160 / 174
页数:15
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