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O-GlcNAcase targets pyruvate kinase M2 to regulate tumor growth

Oncogene volume 39, pages 560–573 (2020)Cite this article

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Abstract

Cancer cells are known to adopt aerobic glycolysis in order to fuel tumor growth, but the molecular basis of this metabolic shift remains largely undefined. O-GlcNAcase (OGA) is an enzyme harboring O-linked β-N-acetylglucosamine (O-GlcNAc) hydrolase and cryptic lysine acetyltransferase activities. Here, we report that OGA is upregulated in a wide range of human cancers and drives aerobic glycolysis and tumor growth by inhibiting pyruvate kinase M2 (PKM2). PKM2 is dynamically O-GlcNAcylated in response to changes in glucose availability. Under high glucose conditions, PKM2 is a target of OGA-associated acetyltransferase activity, which facilitates O-GlcNAcylation of PKM2 by O-GlcNAc transferase (OGT). O-GlcNAcylation inhibits PKM2 catalytic activity and thereby promotes aerobic glycolysis and tumor growth. These studies define a causative role for OGA in tumor progression and reveal PKM2 O-GlcNAcylation as a metabolic rheostat that mediates exquisite control of aerobic glycolysis.

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References

  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    CAS  PubMed  Google Scholar 

  2. Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012;21:297–308.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.

    Google Scholar 

  4. Hart GW, Housley MP, Slawson C. Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature. 2007;446:1017–22.

    CAS  PubMed  Google Scholar 

  5. Yang X, Qian K. Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol. 2017;18:452–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Bond MR, Hanover JA. O-GlcNAc cycling: a link between metabolism and chronic disease. Annu Rev Nutr. 2013;33:205–29.

    CAS  PubMed  Google Scholar 

  7. Ong Q, Han W, Yang X. O-GlcNAc as an integrator of signaling pathways. Front Endocrinol. 2018;9:599.

    Google Scholar 

  8. Ruan HB, Singh JP, Li MD, Wu J, Yang X. Cracking the O-GlcNAc code in metabolism. Trends Endocrinol Metab. 2013;24:301–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Li MD, Ruan HB, Hughes ME, Lee JS, Singh JP, Jones SP, et al. O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination. Cell Metab. 2013;17:303–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Ruan HB, Han X, Li MD, Singh JP, Qian K, Azarhoush S, et al. O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1alpha stability. Cell Metab. 2012;16:226–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Ruan HB, Dietrich MO, Liu ZW, Zimmer MR, Li MD, Singh JP, et al. O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell. 2014;159:306–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Yang X, Ongusaha PP, Miles PD, Havstad JC, Zhang F, So WV, et al. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature. 2008;451:964–9.

    CAS  PubMed  Google Scholar 

  13. Zhang K, Yin R, Yang X. O-GlcNAc: a bittersweet switch in liver. Front Endocrinol. 2014;5:221.

    Google Scholar 

  14. Caldwell SA, Jackson SR, Shahriari KS, Lynch TP, Sethi G, Walker S, et al. Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1. Oncogene. 2010;29:2831–42.

    CAS  PubMed  Google Scholar 

  15. Qian K, Wang S, Fu M, Zhou J, Singh JP, Li MD. et al. Transcriptional regulation of O-GlcNAc homeostasis is disrupted in pancreatic cancer. J Biol Chem. 2018;293:13989–4000.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Singh JP, Zhang K, Wu J, Yang X. O-GlcNAc signaling in cancer metabolism and epigenetics. Cancer Lett. 2015;356:244–50.

    CAS  PubMed  Google Scholar 

  17. Slawson C, Hart GW. O-GlcNAc signalling: implications for cancer cell biology. Nat Rev Cancer. 2011;11:678–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Yang YR, Jang HJ, Yoon S, Lee YH, Nam D, Kim IS, et al. OGA heterozygosity suppresses intestinal tumorigenesis in Apc(min/+) mice. Oncogenesis. 2014;3:e109.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Ferrer CM, Lynch TP, Sodi VL, Falcone JN, Schwab LP, Peacock DL, et al. O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway. Mol Cell. 2014;54:820–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA 3rd, et al. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science. 2012;337:975–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hayakawa K, Hirosawa M, Tabei Y, Arai D, Tanaka S, Murakami N, et al. Epigenetic switching by the metabolism-sensing factors in the generation of orexin neurons from mouse embryonic stem cells. J Biol Chem. 2013;288:17099–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Toleman C, Paterson AJ, Whisenhunt TR, Kudlow JE. Characterization of the histone acetyltransferase (HAT) domain of a bifunctional protein with activable O-GlcNAcase and HAT activities. J Biol Chem. 2004;279:53665–73.

    CAS  PubMed  Google Scholar 

  23. Yang W, Lu Z. Regulation and function of pyruvate kinase M2 in cancer. Cancer Lett. 2013;339:153–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol. 2012;8:839–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ashizawa K, Willingham MC, Liang CM, Cheng SY. In vivo regulation of monomer-tetramer conversion of pyruvate kinase subtype M2 by glucose is mediated via fructose 1,6-bisphosphate. J Biol Chem. 1991;266:16842–6.

    CAS  PubMed  Google Scholar 

  26. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452:230–3.

    CAS  PubMed  Google Scholar 

  27. Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature. 2008;452:181–6.

    CAS  PubMed  Google Scholar 

  28. Hitosugi T, Kang S, Vander Heiden MG, Chung TW, Elf S, Lythgoe K, et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal. 2009;2:ra73.

    PubMed  PubMed Central  Google Scholar 

  29. Lv L, Li D, Zhao D, Lin R, Chu Y, Zhang H, et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol Cell. 2011;42:719–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Lv L, Xu YP, Zhao D, Li FL, Wang W, Sasaki N, et al. Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization. Mol Cell. 2013;52:340–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Investig. 2008;118:3930–42.

    CAS  PubMed  Google Scholar 

  32. Whisenhunt TR, Yang X, Bowe DB, Paterson AJ, Van Tine BA, Kudlow JE. Disrupting the enzyme complex regulating O-GlcNAcylation blocks signaling and development. Glycobiology. 2006;16:551–63.

    CAS  PubMed  Google Scholar 

  33. Krzeslak A, Forma E, Bernaciak M, Romanowicz H, Brys M. Gene expression of O-GlcNAc cycling enzymes in human breast cancers. Clin Exp Med. 2012;12:61–5.

    CAS  PubMed  Google Scholar 

  34. He Y, Roth C, Turkenburg JP, Davies GJ. Three-dimensional structure of a Streptomyces sviceus GNAT acetyltransferase with similarity to the C-terminal domain of the human GH84 O-GlcNAcase. Acta Crystallogr D Biol Crystallogr. 2014;70:186–95.

    CAS  PubMed  Google Scholar 

  35. Rao FV, Schuttelkopf AW, Dorfmueller HC, Ferenbach AT, Navratilova I, van Aalten DM. Structure of a bacterial putative acetyltransferase defines the fold of the human O-GlcNAcase C-terminal domain. Open Biol. 2013;3:130021.

    PubMed  PubMed Central  Google Scholar 

  36. Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol. 2012;14:1295–304.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science. 2010;329:1492–9.

    PubMed Central  Google Scholar 

  38. Bowe DB, Sadlonova A, Toleman CA, Novak Z, Hu Y, Huang P, et al. O-GlcNAc integrates the proteasome and transcriptome to regulate nuclear hormone receptors. Mol Cell Biol. 2006;26:8539–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Luo J, Deng ZL, Luo X, Tang N, Song WX, Chen J, et al. A protocol for rapid generation of recombinant adenoviruses using the AdEasy system. Nat Protoc. 2007;2:1236–47.

    CAS  PubMed  Google Scholar 

  40. Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro. Nat Protoc. 2006;1:2315–9.

    CAS  PubMed  Google Scholar 

  41. Patel AB, de Graaf RA, Mason GF, Rothman DL, Shulman RG, Behar KL. The contribution of GABA to glutamate/glutamine cycling and energy metabolism in the rat cortex in vivo. Proc Natl Acad Sci USA. 2005;102:5588–93.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Jinbo Yang for providing the Flag-PKM2 plasmid and shPKM2 lentivirus. We thank Dr. Julie T. Feldstein for helping with immunohistochemical analysis of human cancer tissues. We thank Dr. Neeraj Tiwari for helping with sucrose density gradient ultracentrifugation. This work was supported by NIH R01 DK089098, P01 DK057751, Yale Comprehensive Cancer Center Pilot Grant, and American Cancer Society Research Scholar Grant to XY.

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Authors and Affiliations

  1. Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06519, USA

    Jay Prakash Singh, Kevin Qian, Jeong-Sang Lee, Bichen Zhang, Qunxiang Ong, Weiming Ni, Hai-Bin Ruan, Min-Dian Li, Kaisi Zhang, Jing Wu & Xiaoyong Yang

  2. Department of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06519, USA

    Jay Prakash Singh, Kevin Qian, Jeong-Sang Lee, Bichen Zhang, Qunxiang Ong, Weiming Ni, Hai-Bin Ruan, Min-Dian Li, Kaisi Zhang, Jing Wu & Xiaoyong Yang

  3. Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06519, USA

    Kevin Qian, Min-Dian Li, Kaisi Zhang & Xiaoyong Yang

  4. State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi’an, 710032, Shaanxi, China

    Jinfeng Zhou, Mingzuo Jiang & Yongzhan Nie

  5. Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Xuemei Han & John R. Yates III

  6. Singapore Bioimaging Consortium, Singapore, Singapore

    Qunxiang Ong, Zhaobing Ding, Philip Lee & Weiping Han

  7. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Kamini Singh & Hans-Guido Wendel

  8. School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, 710049, Shaanxi, China

    Jing Wu

  9. Department of Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06519, USA

    Raimund I. Herzog & Robert S. Sherwin

  10. Department of Immunobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06519, USA

    Susan Kaech

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Correspondence to Xiaoyong Yang.

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Singh, J.P., Qian, K., Lee, JS. et al. O-GlcNAcase targets pyruvate kinase M2 to regulate tumor growth. Oncogene 39, 560–573 (2020). https://doi.org/10.1038/s41388-019-0975-3

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