TY - JOUR
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
N1 - Publisher Copyright:
© 2019, The Author(s).
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.
UR - https://www.scopus.com/pages/publications/85066601943
UR - https://www.scopus.com/pages/publications/85066601943#tab=citedBy
U2 - 10.1038/s41467-019-10352-4
DO - 10.1038/s41467-019-10352-4
M3 - Article
C2 - 31160585
AN - SCOPUS:85066601943
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2399
ER -