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

Author

Listed:
  • Yueming Zhu

    (Northwestern University)

  • Xianghui Zou

    (Northwestern University
    Northwestern University)

  • Angela E. Dean

    (Northwestern University)

  • Joseph O’ Brien

    (Northwestern University)

  • Yucheng Gao

    (Northwestern University
    Northwestern University)

  • Elizabeth L. Tran

    (Northwestern University)

  • Seong-Hoon Park

    (Northwestern University
    Korea Institute of Toxicology (KIT))

  • 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
    Northwestern University
    Northwestern University)

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.

Suggested Citation

  • 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, 2019. "Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10352-4
    DOI: 10.1038/s41467-019-10352-4
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