Volume 31, No 1, Jan 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 1, January 2021: 80-93

ORIGINAL ARTICLES

Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle

Jing Liu^1,2,† , Yunhua Peng^2,† , Le Shi^2,† , Lixin Wan^1,3 , Hiroyuki Inuzuka¹ , Jiangang Lon² , Jianping Guo^1,4 , Jinfang Zhang^1,5 , Min Yuan⁶ , Shuangxi Zhang² , Xun Wang^2,7 , Jing Gao² , Xiangpeng Dai¹ , Shozo Furumoto⁸ , Lijun Jia⁹ , Pier Paolo Pandolf¹⁰ , John M. Asara⁶ , William G. Kaelin Jr^11,12 , Jiankang Liu^2,* , Wenyi Wei^1,*

¹Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
²Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi 710049, China
³Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
⁴Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
⁵Medical Research Institute, School of Medicine, Wuhan University, Wuhan, Hubei 430071, China
⁶Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
⁷Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
⁸Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Tohoku University, Sendai 980-8578, Japan
⁹Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
¹⁰Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
¹¹Howard Hughes Medical Institute, Chevy Chase, MD, USA
¹²Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
^†These authors contributed equally
Correspondence: Jiankang Liu(j.liu@mail.xjtu.edu.cn)Wenyi Wei(wwei2@bidmc.harvard.edu)

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.

https://doi.org/10.1038/s41422-020-0372-z

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