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EMBO Rep. 2018 May;19(5). pii: e45124. doi: 10.15252/embr.201745124. Epub 2018 Feb 28.

SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer.

Chen XF1,2,3, Tian MX4,5, Sun RQ1,2,3, Zhang ML1,2,3, Zhou LS1,2,3, Jin L4,5, Chen LL1,2,3, Zhou WJ1,2,3, Duan KL1,2,3, Chen YJ1,2,3, Gao C1,2,3, Cheng ZL1,2,3, Wang F1,2,3, Zhang JY1,2,3, Sun YP1,2,3, Yu HX1,2,3, Zhao YZ6, Yang Y6, Liu WR4,5, Shi YH4,5, Xiong Y1,2,3,7, Guan KL1,2,3,8, Ye D9,2,3,10.

Author information

1
Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China.
2
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
3
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
4
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
5
Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
6
School of Pharmacy, East China University of Science and Technology, Shanghai, China.
7
Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
8
Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
9
Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Shanghai, China yedan@fudan.edu.cn.
10
Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.

Abstract

Peroxisomes account for ~35% of total H2O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid β-oxidation and a major producer of H2O2 ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT5 increases H2O2 production and oxidative DNA damage, which can be alleviated by ACOX1 knockdown. We show that SIRT5 downregulation is associated with increased succinylation and activity of ACOX1 and oxidative DNA damage response in hepatocellular carcinoma (HCC). Our study reveals a novel role of SIRT5 in inhibiting peroxisome-induced oxidative stress, in liver protection, and in suppressing HCC development.

KEYWORDS:

ACOX1; SIRT5; liver cancer; oxidative stress; succinylation

PMID:
29491006
PMCID:
PMC5934778
DOI:
10.15252/embr.201745124
[Indexed for MEDLINE]
Free PMC Article

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