机构：[1]Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA[2]Center for Mitochondrial Biology and Medicine, The KeyLaboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’anJiaotong University, Xi’an, Shaanxi 710049, China[3]Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA[4]Institute ofPrecision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China中山大学附属第一医院[5]Medical Research Institute, School of Medicine, WuhanUniversity, Wuhan, Hubei 430071, China[6]Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess MedicalCenter, Harvard Medical School, Boston, MA 02215, USA[7]Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA[8]Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Tohoku University, Sendai 980-8578, Japan[9]Cancer Institute, Longhua Hospital, ShanghaiUniversity of Traditional Chinese Medicine, Shanghai 200032, China[10]Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine,Harvard Medical School, Boston, MA 02215, USA[11]Howard Hughes Medical Institute, Chevy Chase, MD, USA[12]Department of Medical Oncology, Dana-Farber CancerInstitute, Harvard Medical School, Boston, MA, USA
Whether glucose is predominantly metabolized via oxidative phosphorylation or glycolysis differs between quiescent versus proliferating cells, including tumor cells. However, how glucose metabolism is coordinated with cell cycle in mammalian cells remains elusive. Here, we report that mammalian cells predominantly utilize the tricarboxylic acid (TCA) cycle in G1 phase, but prefer glycolysis in S phase. Mechanistically, coupling cell cycle with metabolism is largely achieved by timely destruction of IDH1/2, key TCA cycle enzymes, in a Skp2-dependent manner. As such, depleting SKP2 abolishes cell cycle-dependent fluctuation of IDH1 protein abundance, leading to reduced glycolysis in S phase. Furthermore, elevated Skp2 abundance in prostate cancer cells destabilizes IDH1 to favor glycolysis and subsequent tumorigenesis. Therefore, our study reveals a mechanistic link between two cancer hallmarks, aberrant cell cycle and addiction to glycolysis, and provides the underlying mechanism for the coupling of metabolic fluctuation with periodic cell cycle in mammalian cells.
基金：
This work was supported in part by the NIH grants (CA229307 and CA200573 to W.W.;
CA183914 to L.W.; R01CA068490, P50CA101942 and R35CA210068 to W.G.K.), the
National Basic Research Program of China (2015CB553602 to J.K.L.; 2015CB856302 to J.G.
L.), the National Natural Science Foundation of China (91649106, 31570777, 31770917 and
31700684 to J.K.L.; 81802787 to Y.P.). Fundamental Research Funds for the Central
Universities (08143008 and 08143101 to J.K.L.; zrzd2017013 to J.G.L.) and American Cancer
Society (to H.I.)
第一作者机构：[1]Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA[2]Center for Mitochondrial Biology and Medicine, The KeyLaboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’anJiaotong University, Xi’an, Shaanxi 710049, China
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Liu Jing,Peng Yunhua,Shi Le,et al.Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle.[J].CELL RESEARCH.2021,31(1):80-93.doi:10.1038/s41422-020-0372-z.
APA：
Liu Jing,Peng Yunhua,Shi Le,Wan Lixin,Inuzuka Hiroyuki...&Wei Wenyi.(2021).Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle..CELL RESEARCH,31,(1)
MLA：
Liu Jing,et al."Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle.".CELL RESEARCH 31..1(2021):80-93
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