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

Su，Yang1; Luo，Yifan1,9; Zhang，Peitao2; Lin，Hong1; Pu，Weijie1; Zhang，Hongyun1; Wang，Huifang1; Hao，Yi3; Xiao，Yihang4; Zhang，Xiaozhe1; Wei，Xiayun1; Nie，Siyue1; Zhang，Keren5; Fu，Qiuyu6; Chen，Hao7; Huang，Niu6; Ren，Yan8; Wu，Mingxuan4; Chow，Billy Kwok Chong9; Chen，Xing3; Jin，Wenfei1; Wang，Fengchao6; Zhao，Li2; Rao，Feng1

2023-07-06

10.1016/j.molcel.2023.06.010

Molecular Cell   Impact Factor & Quartile

1097-2765

1097-4164

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 E3 ligase, which targets p53 to derepress glycolytic enzymes. A genetic or pharmacologic disruption of the O-GlcNAc-CK2-CSN2-CRL4 axis abrogates glucose-induced p53 degradation and cancer cell proliferation. Diet-induced overnutrition upregulates the CRL4-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-mediated p53 degradation. Such mutation-independent p53 checkpoint bypass may represent the carcinogenic origin and targetable vulnerability of hyperglycemia-driven cancer.

CK2 CRL4COP1 CSN glucose sensing glycometabolism neddylation O-GlcNAcylation overnutrition-associated cancer p53 degradation ubiquitylation

SCI

English

NI Journal Papers ; NI论文

First ; Corresponding

Guangdong Science and Technology Department[2022A1515010830];National Natural Science Foundation of China[31872798];National Natural Science Foundation of China[32122026];National Natural Science Foundation of China[32270831];National Natural Science Foundation of China[82073052];National Natural Science Foundation of China[82273078];National Natural Science Foundation of China[91853129];Science, Technology and Innovation Commission of Shenzhen Municipality[JCYJ20220530114010022];Science, Technology and Innovation Commission of Shenzhen Municipality[JCYJ20220530114802006];Science, Technology and Innovation Commission of Shenzhen Municipality[JCYJ20220818095605011];Science, Technology and Innovation Commission of Shenzhen Municipality[RCJC20221008092757096];

Biochemistry & Molecular Biology ; Cell Biology

Biochemistry & Molecular Biology ; Cell Biology

WOS:001041798300001

CELL PRESS

MOLECULAR BIOLOGY & GENETICS

2-s2.0-85164269561

Scopus

1.School of Life Sciences,Southern University of Science and Technology,Shenzhen,Guangdong,China
2.Department of Thyroid and Neck Oncology,National Clinical Research Center for Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin's Clinical Research Center for Cancer,Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Tianjin Medical University Cancer Institute and Hospital,Tianjin Medical University,Tianjin,China
3.College of Chemistry and Molecular Engineering,Peking University,Beijing,100871,China
4.School of Science,Westlake University,Westlake Laboratory of Life Sciences and Biomedicine,Institute of Natural Sciences,Westlake Institute for Advanced Study,Hangzhou,Zhejiang,China
5.BGI-Shenzhen,Shenzhen,Beishan Industrial Zone 11th building, Yantian District, Guangdong,518083,China
6.National Institute of Biological Sciences,Tsinghua Institute of Multidisciplinary Biomedical Research,Tsinghua University,Beijing,102206,China
7.Department of Human Cell Biology and Genetics,School of Medicine,Southern University of Science and Technology,Shenzhen,Guangdong,China
8.Experiment Center for Science and Technology,Shanghai University of Traditional Chinese Medicine,Shanghai,201203,China
9.School of Biological Sciences,The University of Hong Kong,Pokfulam,Hong Kong

Su，Yang,Luo，Yifan,Zhang，Peitao,et al. Glucose-induced CRL4COP1-p53 axis amplifies glycometabolism to drive tumorigenesis[J]. Molecular Cell,2023,83(13):2316-2331.e7.

Su，Yang.,Luo，Yifan.,Zhang，Peitao.,Lin，Hong.,Pu，Weijie.,...&Rao，Feng.(2023).Glucose-induced CRL4COP1-p53 axis amplifies glycometabolism to drive tumorigenesis.Molecular Cell,83(13),2316-2331.e7.

Su，Yang,et al."Glucose-induced CRL4COP1-p53 axis amplifies glycometabolism to drive tumorigenesis".Molecular Cell 83.13(2023):2316-2331.e7.