Cancer-cell-secreted miR-122 suppresses O-GlcNAcylation to promote skeletal muscle proteolysis

A decline in skeletal muscle mass and low muscular strength are prognostic factors in advanced human cancers. Here we found that breast cancer suppressed O-linked N-acetylglucosamine (O-GlcNAc) protein modification in muscle through extracellular-vesicle-encapsulated miR-122, which targets O-GlcNAc...

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Published inNature cell biology Vol. 24; no. 5; pp. 793 - 804
Main Authors Yan, Wei, Cao, Minghui, Ruan, Xianhui, Jiang, Li, Lee, Sylvia, Lemanek, Adriana, Ghassemian, Majid, Pizzo, Donald P, Wan, Yuhao, Qiao, Yueqing, Chin, Andrew R, Duggan, Erika, Wang, Dong, Nolan, John P, Esko, Jeffrey D, Schenk, Simon, Wang, Shizhen Emily
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 01.05.2022
Subjects
Breast cancer
Calcium ions
Calpain
Cancer
Desmin
Extracellular vesicles
Filaments
Hypoxia
Lactic acid
Muscle contraction
Muscle strength
Muscles
Musculoskeletal system
N-Acetylglucosamine
O-GlcNAcylation
Phosphorylation
Protease
Proteasomes
Proteinase
Proteins
Proteolysis
Ryanodine receptors
Skeletal muscle
Tumors
Ubiquitination
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Summary:A decline in skeletal muscle mass and low muscular strength are prognostic factors in advanced human cancers. Here we found that breast cancer suppressed O-linked N-acetylglucosamine (O-GlcNAc) protein modification in muscle through extracellular-vesicle-encapsulated miR-122, which targets O-GlcNAc transferase (OGT). Mechanistically, O-GlcNAcylation of ryanodine receptor 1 (RYR1) competed with NEK10-mediated phosphorylation and increased K48-linked ubiquitination and proteasomal degradation; the miR-122-mediated decrease in OGT resulted in increased RYR1 abundance. We further found that muscular protein O-GlcNAcylation was regulated by hypoxia and lactate through HIF1A-dependent OGT promoter activation and was elevated after exercise. Suppressed O-GlcNAcylation in the setting of cancer, through increasing RYR1, led to higher cytosolic Ca and calpain protease activation, which triggered cleavage of desmin filaments and myofibrillar destruction. This was associated with reduced skeletal muscle mass and contractility in tumour-bearing mice. Our findings link O-GlcNAcylation to muscular protein homoeostasis and contractility and reveal a mechanism of cancer-associated muscle dysregulation.
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Author Contributions Statement
S.E.W., S.S., and W.Y. conceived ideas. S.E.W., S.S., W.Y., and J.D.E. contributed to project planning and manuscript writing. W.Y. and S.E.W. designed and performed most of the experiments. S.L., A.L., and S.S. performed muscle mechanics tests and analyses. M.G. assisted with mass spectrometry analysis. M.C. and A.R.C. assisted with cell line construction. M.C., X.R., L.J., and Y.W. assisted with mouse experiments. Y.Q. assisted with data analysis. E.D. and J.P.N. performed EV characterization by flow cytometry. D.P.P. assisted with tissue processing and histological analyses. D.W. contributed to characterization of RYR1 PTMs and functional domains.
ISSN:1465-7392
1476-4679
DOI:10.1038/s41556-022-00893-0