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Nat Commun. 2019 Jun 3;10(1):2399. doi: 10.1038/s41467-019-10352-4.

Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter.

Author information

1
Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
2
Driskill Graduate Program in Life Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
3
Department of General and Applied Toxicology, Innovative Toxicology Research Center, Korea Institute of Toxicology (KIT), Daejeon, 34114, Korea.
4
Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
5
Scientific Editing Solutions, Walworth, WI, 53184, USA.
6
Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
7
Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. david.gius@northwestern.edu.
8
Driskill Graduate Program in Life Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. david.gius@northwestern.edu.
9
Department of Pharmacology, Robert H. Lurie Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. david.gius@northwestern.edu.

Abstract

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.

PMID:
31160585
PMCID:
PMC6546705
DOI:
10.1038/s41467-019-10352-4
[Indexed for MEDLINE]
Free PMC Article

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