Open AccessLysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter
Author(s) -
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,
K.J.F. Satchell,
Nobuo Horikoshi,
Marcelo G. Bonini,
David Gius
Publication year - 2019
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/s41467-019-10352-4
Subject(s) - carcinogenesis , homotetramer , superoxide dismutase , biology , acetylation , peroxidase , cancer research , microbiology and biotechnology , chemistry , biochemistry , enzyme , protein subunit , gene
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.