1. Cancer-cell-secreted miR-122 suppresses O-GlcNAcylation to promote skeletal muscle proteolysis
- Author
-
Wei Yan, Minghui Cao, Xianhui Ruan, Li Jiang, Sylvia Lee, Adriana Lemanek, Majid Ghassemian, Donald P. Pizzo, Yuhao Wan, Yueqing Qiao, Andrew R. Chin, Erika Duggan, Dong Wang, John P. Nolan, Jeffrey D. Esko, Simon Schenk, and Shizhen Emily Wang
- Subjects
N-Acetylglucosaminyltransferases ,Medical and Health Sciences ,Acetylglucosamine ,Mice ,Rare Diseases ,Neoplasms ,Breast Cancer ,Animals ,Humans ,2.1 Biological and endogenous factors ,Aetiology ,Muscle, Skeletal ,Protein Processing ,Cancer ,Post-Translational ,Ryanodine Receptor Calcium Release Channel ,Cell Biology ,Skeletal ,Biological Sciences ,MicroRNAs ,Musculoskeletal ,Proteolysis ,Muscle ,Protein Processing, Post-Translational ,Developmental Biology - Abstract
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 Ca2+ 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.
- Published
- 2022