TY - JOUR
T1 - Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter
AU - Zhu, Yueming
AU - Zou, Xianghui
AU - Dean, Angela E.
AU - Brien, Joseph O’
AU - Gao, Yucheng
AU - Tran, Elizabeth L.
AU - Park, Seong Hoon
AU - Liu, Guoxiang
AU - Kieffer, Matthew B.
AU - Jiang, Haiyan
AU - Stauffer, Melissa E.
AU - Hart, Robert
AU - Quan, Songhua
AU - Satchell, Karla J.F.
AU - Horikoshi, Nobuo
AU - Bonini, Marcelo
AU - Gius, David R
N1 - Funding Information:
D.G. is supported by 2R01CA152601-A1, 1R01CA152799-01A1, 1R01CA168292-01A1, 1R01CA214025-01, the Avon Breast Cancer Foundation, the Lynn Sage Cancer Research Foundation, the Zell Family Foundation, and the Chicago Biomedical Consortium, as well the Searle Funds at The Chicago Community Trust. M.B. is supported by a U.S. Department of Defense grant 67263-RT-REP and an NIH 1RO1HL125356 award. Y.Z. is supported by a Robert H. Lurie Comprehensive Cancer Center Translation Bridge Fellowship Award. Y.G. was supported in part by the Chicago Cancer Baseball Charities at the Lurie Cancer Center of Northwestern University. K.J.F.S. is supported by 5R01AI092825-07. Imaging work was performed at the Northwestern University Center for Advanced Microscopy, which is generously supported by NCI CCSG P30 CA060553, awarded to the Robert H. Lurie Comprehensive Cancer Center. Proteomics services were performed by the Northwestern Proteomics Core Facility, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569. The structural analyses of MnSOD were performed at the Northwestern University Structural Biology Facility, which is generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. The bacterial MnSOD expression and lysine acetylation tRNA mutant plasmids were a gift from Jiangyun Wang, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Manganese superoxide dismutase (MnSOD) functions as a tumor suppressor; however, once tumorigenesis occurs, clinical data suggest MnSOD levels correlate with more aggressive human tumors, implying a potential dual function of MnSOD in the regulation of metabolism. Here we show, using in vitro transformation and xenograft growth assays that the MnSOD-K68 acetylation (Ac) mimic mutant (MnSODK68Q) functions as a tumor promoter. Interestingly, in various breast cancer and primary cell types the expression of MnSODK68Q is accompanied with a change of MnSOD’s stoichiometry from a known homotetramer complex to a monomeric form. Biochemical experiments using the MnSOD-K68Q Ac-mimic, or physically K68-Ac (MnSOD-K68-Ac), suggest that these monomers function as a peroxidase, distinct from the established MnSOD superoxide dismutase activity. MnSODK68Q expressing cells exhibit resistance to tamoxifen (Tam) and cells selected for Tam resistance exhibited increased K68-Ac and monomeric MnSOD. These results suggest a MnSOD-K68-Ac metabolic pathway for Tam resistance, carcinogenesis and tumor progression.
AB - Manganese superoxide dismutase (MnSOD) functions as a tumor suppressor; however, once tumorigenesis occurs, clinical data suggest MnSOD levels correlate with more aggressive human tumors, implying a potential dual function of MnSOD in the regulation of metabolism. Here we show, using in vitro transformation and xenograft growth assays that the MnSOD-K68 acetylation (Ac) mimic mutant (MnSODK68Q) functions as a tumor promoter. Interestingly, in various breast cancer and primary cell types the expression of MnSODK68Q is accompanied with a change of MnSOD’s stoichiometry from a known homotetramer complex to a monomeric form. Biochemical experiments using the MnSOD-K68Q Ac-mimic, or physically K68-Ac (MnSOD-K68-Ac), suggest that these monomers function as a peroxidase, distinct from the established MnSOD superoxide dismutase activity. MnSODK68Q expressing cells exhibit resistance to tamoxifen (Tam) and cells selected for Tam resistance exhibited increased K68-Ac and monomeric MnSOD. These results suggest a MnSOD-K68-Ac metabolic pathway for Tam resistance, carcinogenesis and tumor progression.
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U2 - 10.1038/s41467-019-10352-4
DO - 10.1038/s41467-019-10352-4
M3 - Article
C2 - 31160585
AN - SCOPUS:85066601943
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2399
ER -
