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

Yueming Zhu, Xianghui Zou, Angela E. Dean, Joseph O’ Brien, Yucheng Gao, Elizabeth L. Tran, Seong-Hoon Park, Guoxiang Liu, Matthew B. Kieffer, Haiyan Jiang, Melissa E. Stauffer, Robert Hart, Songhua Quan, Karla J. F. Satchell, Nobuo Horikoshi, Marcelo Bonini and David Gius ()
Additional contact information
Yueming Zhu: Northwestern University
Xianghui Zou: Northwestern University
Angela E. Dean: Northwestern University
Joseph O’ Brien: Northwestern University
Yucheng Gao: Northwestern University
Elizabeth L. Tran: Northwestern University
Seong-Hoon Park: Northwestern University
Guoxiang Liu: Northwestern University
Matthew B. Kieffer: Northwestern University
Haiyan Jiang: Northwestern University
Melissa E. Stauffer: Scientific Editing Solutions
Robert Hart: University of Illinois at Chicago
Songhua Quan: Northwestern University
Karla J. F. Satchell: Northwestern University
Nobuo Horikoshi: Northwestern University
Marcelo Bonini: University of Illinois at Chicago
David Gius: Northwestern University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10352-4

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