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

ABSTRACT: Decline in skeletal muscle mass and lower muscular strength are prognostic factors in advanced human cancers. We found that breast cancer suppressed O-linked N-acetylglucosamine (O-GlcNAc) protein modification in skeletal muscle through extracellular-vesicle-encapsulated miR-122 that targeted O-GlcNAc transferase (OGT). Specifically, O-GlcNAcylation of ryanodine receptor 1 (RYR1) Ca2+ release channel competed with NEK10-mediated phosphorylation and increased K48-linked ubiquitination and proteasomal degradation, whereas O-GlcNAcylation of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA3) increased K63-linked ubiquitination and elevated protein level. Muscular protein O-GlcNAcylation was regulated by hypoxia and lactate through HIF1A-dependent OGT promoter activation, and elevated after exercise. Suppressed O-GlcNAcylation in the setting of cancer, especially through increased RYR1 protein, led to Ca2+ leak and calpain protease activation to trigger myofibrillar protein cleavage. This was associated with reduced skeletal muscle mass and contractility in tumor-bearing mice. Our findings link O-GlcNAcylation to muscular protein homeostasis and contractility, and reveal a mechanism of cancer-associated muscle dysregulation.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

DISEASE(S): Female Breast Cancer

SUBMITTER: Majid Ghassemian  

LAB HEAD: Emily Wang1

PROVIDER: PXD021232 | Pride | 2023-03-10

REPOSITORIES: Pride