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Article: Glucose-induced CRL4COP1-p53 axis amplifies glycometabolism to drive tumorigenesis

TitleGlucose-induced CRL4COP1-p53 axis amplifies glycometabolism to drive tumorigenesis
Authors
KeywordsCK2
CRL4COP1
CSN
glucose sensing
glycometabolism
neddylation
O-GlcNAcylation
overnutrition-associated cancer
p53 degradation
ubiquitylation
Issue Date29-Jun-2023
PublisherCell Press
Citation
Molecular Cell, 2023, v. 83, n. 13, p. 2316-2331 How to Cite?
Abstract

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 CRL4COP1 E3 ligase, which targets p53 to derepress glycolytic enzymes. A genetic or pharmacologic disruption of the O-GlcNAc-CK2-CSN2-CRL4COP1 axis abrogates glucose-induced p53 degradation and cancer cell proliferation. Diet-induced overnutrition upregulates the CRL4COP1-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 CRL4COP1-mediated p53 degradation. Such mutation-independent p53 checkpoint bypass may represent the carcinogenic origin and targetable vulnerability of hyperglycemia-driven cancer.


Persistent Identifierhttp://hdl.handle.net/10722/329147
ISSN
2023 Impact Factor: 14.5
2023 SCImago Journal Rankings: 9.332
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSu, Yang-
dc.contributor.authorLuo, Yifan-
dc.contributor.authorZhang, Peitao-
dc.contributor.authorLin, Hong-
dc.contributor.authorPu, Weijie-
dc.contributor.authorZhang, Hongyun-
dc.contributor.authorWang, Huifang-
dc.contributor.authorHao, Yi-
dc.contributor.authorXiao, Yihang-
dc.contributor.authorZhang, Xiaozhe-
dc.contributor.authorWei, Xiayun-
dc.contributor.authorNie, Siyue-
dc.contributor.authorZhang, Keren-
dc.contributor.authorFu, Qiuyu-
dc.contributor.authorChen, Hao-
dc.contributor.authorHuang, Niu-
dc.contributor.authorRen, Yan-
dc.contributor.authorWu, Mingxuan-
dc.contributor.authorChow, Billy Kwok Chong-
dc.contributor.authorChen, Xing-
dc.contributor.authorJin, Wenfei-
dc.contributor.authorWang, Fengchao-
dc.contributor.authorZhao, Li-
dc.contributor.authorRao, Feng-
dc.date.accessioned2023-08-05T07:55:39Z-
dc.date.available2023-08-05T07:55:39Z-
dc.date.issued2023-06-29-
dc.identifier.citationMolecular Cell, 2023, v. 83, n. 13, p. 2316-2331-
dc.identifier.issn1097-2765-
dc.identifier.urihttp://hdl.handle.net/10722/329147-
dc.description.abstract<p>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<sup>COP1</sup> E3 ligase, which targets p53 to derepress glycolytic enzymes. A genetic or pharmacologic disruption of the O-GlcNAc-CK2-CSN2-CRL4<sup>COP1</sup> axis abrogates glucose-induced p53 degradation and cancer cell proliferation. Diet-induced overnutrition upregulates the CRL4<sup>COP1</sup>-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<sup>COP1</sup>-mediated p53 degradation. Such mutation-independent p53 checkpoint bypass may represent the carcinogenic origin and targetable vulnerability of hyperglycemia-driven cancer.</p>-
dc.languageeng-
dc.publisherCell Press-
dc.relation.ispartofMolecular Cell-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectCK2-
dc.subjectCRL4COP1-
dc.subjectCSN-
dc.subjectglucose sensing-
dc.subjectglycometabolism-
dc.subjectneddylation-
dc.subjectO-GlcNAcylation-
dc.subjectovernutrition-associated cancer-
dc.subjectp53 degradation-
dc.subjectubiquitylation-
dc.titleGlucose-induced CRL4COP1-p53 axis amplifies glycometabolism to drive tumorigenesis-
dc.typeArticle-
dc.identifier.doi10.1016/j.molcel.2023.06.010-
dc.identifier.scopuseid_2-s2.0-85164269561-
dc.identifier.volume83-
dc.identifier.issue13-
dc.identifier.spage2316-
dc.identifier.epage2331-
dc.identifier.eissn1097-4164-
dc.identifier.isiWOS:001041798300001-
dc.identifier.issnl1097-2765-

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