文献类型：期刊文献

英文题名：SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer

作者：Chen, Xiu-Fei[1,2,3];Tian, Meng-Xin[4,5];Sun, Ren-Qiang[1,2,3];Zhang, Meng-Li[1,2,3];Zhou, Li-Sha[1,2,3];Jin, Lei[4,5];Chen, Lei-Lei[1,2,3];Zhou, Wen-Jie[1,2,3];Duan, Kun-Long[1,2,3];Chen, Yu-Jia[1,2,3];Gao, Chao[1,2,3];Cheng, Zhou-Li[1,2,3];Wang, Fang[1,2,3];Zhang, Jin-Ye[1,2,3];Sun, Yi-Ping[1,2,3];Yu, Hong-Xiu[1,2,3];Zhao, Yu-Zheng[6];Yang, Yi[6];Liu, Wei-Ren[4,5];Shi, Ying-Hong[4,5];Xiong, Yue[1,2,3,7];Guan, Kun-Liang[1,2,3,8,9];Ye, Dan[1,2,3,10]

机构：[1]Shanghai Med Coll, Inst Biomed Sci, Mol & Cell Biol Lab, Shanghai, Peoples R China;[2]Fudan Univ, Key Lab Metab & Mol Med, Minist Educ, Dept Biochem & Mol Biol,Sch Basic Med Sci, Shanghai, Peoples R China;[3]Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, State Key Lab Genet Engn, Shanghai, Peoples R China;[4]Fudan Univ, Zhongshan Hosp, Liver Canc Inst, Dept Liver Surg, Shanghai, Peoples R China;[5]Minist Educ, Key Lab Carcinogenesis & Canc Invas, Shanghai, Peoples R China;[6]East China Univ Sci & Technol, Sch Pharm, Shanghai, Peoples R China;[7]Univ North Carolina Chapel Hill, Dept Biochem & Biophys, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA;[8]Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA;[9]Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA;[10]Fudan Univ, Huashan Hosp, Dept Gen Surg, Shanghai, Peoples R China

年份：2018

卷号：19

期号：5

外文期刊名：EMBO REPORTS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000431633800006)】；

基金：We thank members of the Fudan MCB laboratory for discussions and support throughout this study. This work was supported by the National Key R&D Program of China (No. 2016YFA0501800 to D.Y. and Y.X.), the NSFC grant (No. 81372198 to D.Y.), the 973 Program (No. 2015CB910401 to Y.X.), and the Shanghai Committee of Science and Technology, China (No. 16JC1404000 to D.Y.). This work was also supported by NIH grants (GM067113 and CA063834 to Y.X.; CA196878 and GM51586 to K.L.G.).

语种：英文

外文关键词：ACOX1; liver cancer; oxidative stress; SIRT5; succinylation

摘要：Peroxisomes account for similar to 35% of total H2O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid beta-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.