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

doi:10.1038/s41467-019-10352-4

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 journal › Article

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 (MnSOD^K68Q) functions as a tumor promoter. Interestingly, in various breast cancer and primary cell types the expression of MnSOD^K68Q 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. MnSOD^K68Q 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 language	English (US)
Article number	2399
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10352-4
State	Published - 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

Zhu, Yueming ; Zou, Xianghui ; Dean, Angela E. ; Brien, Joseph O’ ; Gao, Yucheng ; Tran, Elizabeth L. ; Park, Seong Hoon ; Liu, Guoxiang ; Kieffer, Matthew B. ; Jiang, Haiyan ; Stauffer, Melissa E. ; Hart, Robert ; Quan, Songhua ; Satchell, Karla J.F. ; Horikoshi, Nobuo ; Bonini, Marcelo ; Gius, David. / Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter. In: Nature communications. 2019 ; Vol. 10, No. 1.

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title = "Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter",

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{\textquoteright}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.",

author = "Yueming Zhu and Xianghui Zou and Dean, {Angela E.} and Brien, {Joseph O{\textquoteright}} and Yucheng Gao and Tran, {Elizabeth L.} and Park, {Seong Hoon} and Guoxiang Liu and Kieffer, {Matthew B.} and Haiyan Jiang and Stauffer, {Melissa E.} and Robert Hart and Songhua Quan and Satchell, {Karla J.F.} and Nobuo Horikoshi and Marcelo Bonini and David Gius",

year = "2019",

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Zhu, Y, Zou, X, Dean, AE, Brien, JO, Gao, Y, Tran, EL, Park, SH, Liu, G, Kieffer, MB, Jiang, H, Stauffer, ME, Hart, R, Quan, S, Satchell, KJF , Horikoshi, N , Bonini, M & Gius, D 2019, 'Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter', Nature communications, vol. 10, no. 1, 2399. https://doi.org/10.1038/s41467-019-10352-4

Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter. / Zhu, Yueming; Zou, Xianghui; Dean, Angela E.; Brien, Joseph O’; Gao, Yucheng; Tran, Elizabeth L.; Park, Seong Hoon; Liu, Guoxiang; Kieffer, Matthew B.; Jiang, Haiyan; Stauffer, Melissa E.; Hart, Robert; Quan, Songhua; Satchell, Karla J.F.; Horikoshi, Nobuo ; Bonini, Marcelo ; Gius, David.

In: Nature communications, Vol. 10, No. 1, 2399, 01.12.2019.

Research output: Contribution to journal › Article

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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

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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10.1038/s41467-019-10352-4