Glucose-induced CRL4COP1-p53 degradation axis amplifies glycometabolism to drive tumorigenesis

The diabetes-cancer association remains under-explained. 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. 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 up-regulates the CRL4^COP1-p53 axis to promote PyMT-induced mammary tumorigenesis in wildtype but not 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.