| First Author | Su Y | Year | 2023 |
| Journal | Mol Cell | Volume | 83 |
| Issue | 13 | Pages | 2316-2331.e7 |
| PubMed ID | 37390815 | Mgi Jnum | J:338217 |
| Mgi Id | MGI:7511356 | Doi | 10.1016/j.molcel.2023.06.010 |
| Citation | Su Y, et al. (2023) Glucose-induced CRL4(COP1)-p53 axis amplifies glycometabolism to drive tumorigenesis. Mol Cell 83(13):2316-2331.e7 |
| abstractText | The diabetes-cancer association remains underexplained. Here, we describe a glucose-signaling axis that reinforces glucose uptake and glycolysis to consolidate the Warburg effect and overcome tumor suppression. Specifically, glucose-dependent CK2 O-GlcNAcylation impedes its phosphorylation of CSN2, a modification required for the deneddylase CSN to sequester Cullin RING ligase 4 (CRL4). Glucose, therefore, elicits CSN-CRL4 dissociation to assemble the CRL4(COP1) E3 ligase, which targets p53 to derepress glycolytic enzymes. A genetic or pharmacologic disruption of the O-GlcNAc-CK2-CSN2-CRL4(COP1) axis abrogates glucose-induced p53 degradation and cancer cell proliferation. Diet-induced overnutrition upregulates the CRL4(COP1)-p53 axis to promote PyMT-induced mammary tumorigenesis in wild type but not in mammary-gland-specific p53 knockout mice. These effects of overnutrition are reversed by P28, an investigational peptide inhibitor of COP1-p53 interaction. Thus, glycometabolism self-amplifies via a glucose-induced post-translational modification cascade culminating in CRL4(COP1)-mediated p53 degradation. Such mutation-independent p53 checkpoint bypass may represent the carcinogenic origin and targetable vulnerability of hyperglycemia-driven cancer. |
