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.糖尿病与癌症的关联仍有待深入探索。本研究报道了一条葡萄糖信号轴，该信号轴可增强葡萄糖摄取与糖酵解过程，以巩固瓦伯格效应（Warburg effect）并对抗肿瘤抑制。具体而言，葡萄糖依赖的CK2 O-糖基化修饰（O-GlcNAcylation）会阻碍其对CSN2的磷酸化；而该修饰是去NEDD化酶CSN隔离Cullin环连接酶4（Cullin RING Ligase 4, CRL4）所必需的。因此，葡萄糖可诱导CSN与CRL4解离，进而组装CRL4^COP1 E3泛素连接酶，该连接酶靶向p53以解除对糖酵解酶的抑制。对O-GlcNAc-CK2-CSN2-CRL4^COP1轴进行遗传学或药理学干预，可阻断葡萄糖诱导的p53降解与癌细胞增殖。饮食诱导的营养过剩会上调CRL4^COP1-p53轴，从而在野生型小鼠中促进多瘤病毒M型癌基因（PyMT）诱导的乳腺肿瘤发生，但在乳腺组织特异性p53敲除小鼠中无此效应。临床研究中的COP1-p53相互作用肽抑制剂P28可逆转营养过剩的上述作用。综上，糖代谢可通过一条葡萄糖诱导的翻译后修饰级联反应实现自我扩增，最终以CRL4^COP1介导的p53降解告终。这种不依赖突变的p53检查点绕过机制，可能是高血糖驱动癌症的致癌起源与可靶向的脆弱靶点。