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, David Gius*

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Article number2399
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Zhu, Y., Zou, X., Dean, A. E., Brien, J. O., Gao, Y., Tran, E. L., Park, S. H., Liu, G., Kieffer, M. B., Jiang, H., Stauffer, M. E., Hart, R., Quan, S., Satchell, K. J. F., Horikoshi, N., Bonini, M., & Gius, D. (2019). Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter. Nature communications, 10(1), [2399]. https://doi.org/10.1038/s41467-019-10352-4