期刊
NATURE CELL BIOLOGY
卷 24, 期 5, 页码 793-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41556-022-00893-0
关键词
-
类别
资金
- National Institutes of Health (NIH) National Cancer Institute (NCI) [R01CA218140, R01CA206911]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [R21AR072882]
- National Institute of General Medical Sciences (NIGMS) [R01GM102362]
- NIH NCI [P30CA23100, P30CA030199]
Breast cancer suppresses O-GlcNAc protein modification in muscle through miR-122, leading to dysregulated skeletal muscle proteolysis with aberrant Ca2+ levels and calpain protease activation.
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. Yan et al. report that breast cancer cell-derived miR-122 downregulates O-GlcNAcylation of RYR1 and increases its abundance, thereby leading to dysregulated skeletal muscle proteolysis with aberrant Ca2+ levels and calpain protease activation.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据