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

Cell Research volume 31, pages80–93(2021)Cite this article

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A Correction to this article was published on 28 August 2020

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Abstract

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.

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Fig. 1: Mammalian cells adopt different glucose metabolism pathways in different cell cycle stages, primarily utilizing TCA cycle in G1 phase, but relying on glycolysis in S phase.
Fig. 2: The fluctuation of IDH1/2 protein abundances during cell cycle.
Fig. 3: SCFSkp2 promotes IDH1/2 ubiquitination and subsequent degradation, thus dictating cell cycle-dependent metabolic shift.
Fig. 5: Non-degradable IDH1 is resistant to cell cycle-dependent fluctuation in abundance, and restricts cell proliferation.
Fig. 6: Skp2 dedicates the metabolic phenotypes of prostate cancer cell lines in part by promoting IDH1 degradation.
Fig. 7: Skp2 inhibitor represses prostate cancer via shifting cell metabolism from glycolysis to TCA cycle.

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  • 28 August 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

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.). We thank Wangxiao He, Zhanwu Hou and Huadong Liu for their help with the peptide synthesis, thank Evan Chen for his kind help with metabolite labeling, and thank Brian J. North and Wei lab members for critical reading of the manuscript, and members of the Wei, Pandolfi, Kaelin and Liu laboratories for helpful discussions.

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Author notes

  1. These authors contributed equally: Jing Liu, Yunhua Peng, Le Shi

Affiliations

  1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA

    Jing Liu, Lixin Wan, Hiroyuki Inuzuka, Jianping Guo, Jinfang Zhang, Xiangpeng Dai & Wenyi Wei

  2. Center 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

    Jing Liu, Yunhua Peng, Le Shi, Jiangang Long, Shuangxi Zhang, Xun Wang, Jing Gao & Jiankang Liu

  3. Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA

    Lixin Wan

  4. Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China

    Jianping Guo

  5. Medical Research Institute, School of Medicine, Wuhan University, Wuhan, Hubei, 430071, China

    Jinfang Zhang

  6. Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA

    Min Yuan & John M. Asara

  7. Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Xun Wang

  8. Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Tohoku University, Sendai, 980-8578, Japan

    Shozo Furumoto

  9. Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China

    Lijun Jia

  10. Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, 02215, USA

    Pier Paolo Pandolfi

  11. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    William G. Kaelin Jr.

  12. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    William G. Kaelin Jr.

Authors
  1. Jing Liu
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  2. Yunhua Peng
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Contributions

J.L. and Y.P. designed and performed most of the experiments with assistance from L.S., L.W., H.I., J.G.L., J.P.G., J.Z., S.Z., X.W., J.G., X.D., S.F. and L.J., M.Y. and J.M.A. performed the LC-MS/MS metabolomic profiling and mass spectrometry analysis of IDH1 T157 phosphorylation. W.W., J.K.L., P.P.P., and W.G.K. supervised the study. J.L. and W.W. wrote the manuscript. All authors commented on the manuscript.

Corresponding authors

Correspondence to Jiankang Liu or Wenyi Wei.

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Competing interests

W.W. is a co-founder and consultant of the ReKindle Therapeutics. All other authors declare no competing interests.

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Liu, J., Peng, Y., Shi, L. et al. Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle. Cell Res 31, 80–93 (2021). https://doi.org/10.1038/s41422-020-0372-z

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