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CHIP/Stub1 regulates the Warburg effect by promoting degradation of PKM2 in ovarian carcinoma

Oncogene volume 36, pages 4191–4200 (2017)Cite this article

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Abstract

Tumor cells preferentially adopt aerobic glycolysis for their energy supply, a phenomenon known as the Warburg effect. It remains a matter of debate as to how the Warburg effect is regulated during tumor progression. Here, we show that CHIP (carboxyl terminus of Hsc70-interacting protein), a U-box E3 ligase, suppresses tumor progression in ovarian carcinomas by inhibiting aerobic glycolysis. While CHIP is downregulated in ovarian carcinoma, induced expression of CHIP results in significant inhibition of the tumor growth examined by in vitro and in vivo experiments. Reciprocally, depletion of CHIP leads to promotion of tumor growth. By a SiLAD proteomics analysis, we identified pyruvate kinase isoenzyme M2 (PKM2), a critical regulator of glycolysis in tumors, as a target that CHIP mediated for degradation. Accordingly, we show that CHIP regulates PKM2 protein stability and thereafter the energy metabolic processes. Depletion or knockout of CHIP increased the glycolytic products in both tumor and mouse embryonic fibroblast cells. Simultaneously, we observed that CHIP expression inversely correlated with PKM2 levels in human ovarian carcinomas. This study reveals a mechanism that the Warburg effect is regulated by CHIP through its function as an E3 ligase, which mediates the degradation of PKM2 during tumor progression. Our findings shed new light into understanding of ovarian carcinomas and may provide a new therapeutic strategy for ovarian cancer.

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References

  1. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    Article  CAS  PubMed  Google Scholar 

  2. Warburg O . On the origin of cancer cells. Science 1956; 123: 309–314.

    Article  CAS  PubMed  Google Scholar 

  3. Altenberg B, Greulich KO . Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics 2004; 84: 1014–1020.

    Article  CAS  PubMed  Google Scholar 

  4. Israelsen WJ, Vander Heiden MG . Pyruvate kinase: function, regulation and role in cancer. Semin Cell Dev Biol 2015; 43: 43–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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: 230–233.

    Article  CAS  PubMed  Google Scholar 

  6. Chaneton B, Gottlieb E . Rocking cell metabolism: revised functions of the key glycolytic regulator PKM2 in cancer. Trends Biochem Sci 2012; 37: 309–316.

    Article  CAS  PubMed  Google Scholar 

  7. Wong N, Ojo D, Yan J, Tang D . PKM2 contributes to cancer metabolism. Cancer Lett 2015; 356: 184–191.

    Article  CAS  PubMed  Google Scholar 

  8. Kefas B, Comeau L, Erdle N, Montgomery E, Amos S, Purow B . Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells. Neuro Oncol 2010; 12: 1102–1112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sun Q, Chen X, Ma J, Peng H, Wang F, Zha X et al. Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci USA 2011; 108: 4129–4134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Goldberg MS, Sharp PA . Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression. J Exp Med 2012; 209: 217–224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liu AM, Xu Z, Shek FH, Wong KF, Lee NP, Poon RT et al. miR-122 targets pyruvate kinase M2 and affects metabolism of hepatocellular carcinoma. PLoS One 2014; 9: e86872.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Huang L, Yu Z, Zhang T, Zhao X, Huang G . HSP40 interacts with pyruvate kinase M2 and regulates glycolysis and cell proliferation in tumor cells. PLoS One 2014; 9: e92949.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Li Z, Yang P, Li Z . The multifaceted regulation and functions of PKM2 in tumor progression. Biochim Biophys Acta 2014; 1846: 285–296.

    CAS  PubMed  Google Scholar 

  14. Luo W, Semenza GL . Emerging roles of PKM2 in cell metabolism and cancer progression. Trends Endocrinol Metab 2012; 23: 560–566.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 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: 719–730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yu Z, Zhao X, Huang L, Zhang T, Yang F, Xie L et al. Proviral insertion in murine lymphomas 2 (PIM2) oncogene phosphorylates pyruvate kinase M2 (PKM2) and promotes glycolysis in cancer cells. J Biol Chem 2013; 288: 35406–35416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Viana R, Lujan P, Sanz P . The laforin/malin E3-ubiquitin ligase complex ubiquitinates pyruvate kinase M1/M2. BMC Biochem 2015; 16: 24.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Liu K, Li F, Han H, Chen Y, Mao Z, Luo J et al. Parkin regulates the activity of pyruvate kinase M2. J Biol Chem 2016; 291: 10307–10317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Paul I, Ghosh MK . The E3 ligase CHIP: insights into its structure and regulation. BioMed Res Int 2014; 2014: 918183.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sun C, Li HL, Shi ML, Liu QH, Bai J, Zheng JN . Diverse roles of C-terminal Hsp70-interacting protein (CHIP) in tumorigenesis. J Cancer Res Clin Oncol 2014; 140: 189–197.

    Article  CAS  PubMed  Google Scholar 

  21. Kajiro M, Hirota R, Nakajima Y, Kawanowa K, So-ma K, Ito I et al. The ubiquitin ligase CHIP acts as an upstream regulator of oncogenic pathways. Nat Cell Biol 2009; 11: 312–319.

    Article  CAS  PubMed  Google Scholar 

  22. Xin H, Xu X, Li L, Ning H, Rong Y, Shang Y et al. CHIP controls the sensitivity of transforming growth factor-beta signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation. J Biol Chem 2005; 280: 20842–20850.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang Z, Chen J, Guo F, He L, Wu Y, Zeng C et al. A high-temporal resolution technology for dynamic proteomic analysis based on 35S labeling. PLoS One 2008; 3: e2991.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kundrat L, Regan L . Identification of residues on Hsp70 and Hsp90 ubiquitinated by the cochaperone CHIP. J Mol Biol 2010; 395: 587–594.

    Article  CAS  PubMed  Google Scholar 

  25. 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: 1295–1304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chao CC . Mechanisms of p53 degradation. Clin Chim Acta 2014; 438C: 139–147.

    Google Scholar 

  27. Shang Y, Zhao X, Tian B, Wang Y, Ren F, Jia B et al. CHIP/Stub1 interacts with eIF5A and mediates its degradation. Cell Signal 2014; 26: 1098–1104.

    Article  CAS  PubMed  Google Scholar 

  28. Hou J, Deng Q, Zhou J, Zou J, Zhang Y, Tan P et al. CSN6 controls the proliferation and metastasis of glioblastoma by CHIP-mediated degradation of EGFR. Oncogene 2017; 36: 1134–1144.

    Article  CAS  PubMed  Google Scholar 

  29. Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G et al. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 2013; 155: 397–409.

    Article  CAS  PubMed  Google Scholar 

  30. Dayton TL, Gocheva V, Miller KM, Israelsen WJ, Bhutkar A, Clish CB et al. Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma. Genes Dev 2016; 30: 1020–1033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hosios AM, Fiske BP, Gui DY, Vander Heiden MG . Lack of evidence for PKM2 protein kinase activity. Mol Cell 2015; 59: 850–857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang YH, Israelsen WJ, Lee D, Yu VW, Jeanson NT, Clish CB et al. Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. Cell 2014; 158: 1309–1323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Poersch A, Souza LO, Faça VM, Greene LJ, Reis FJCd . Identification of PKM2 as a potential biomarker of high-grade ovarian serous tumor. Mol Cancer Ther 2013; 12: Abstract no. A138.

  34. Li X, Huang M, Zheng H, Wang Y, Ren F, Shang Y et al. CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation. J Cell Biol 2008; 181: 959–972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shang Y, Zhao X, Xu X, Xin H, Li X, Zhai Y et al. CHIP functions an E3 ubiquitin ligase of Runx1. Biochem Biophys Res Commun 2009; 386: 242–246.

    Article  CAS  PubMed  Google Scholar 

  36. Li RF, Shang Y, Liu D, Ren ZS, Chang Z, Sui SF . Differential ubiquitination of Smad1 mediated by CHIP: implications in the regulation of the bone morphogenetic protein signaling pathway. J Mol Biol 2007; 374: 777–790.

    Article  CAS  PubMed  Google Scholar 

  37. Lu D, Wu Y, Wang Y, Ren F, Wang D, Su F et al. CREPT accelerates tumorigenesis by regulating the transcription of cell-cycle-related genes. Cancer Cell 2012; 21: 92–104.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Deyin Guo for providing PKM2 constructs (Wuhan University, China), and Dr Beihua Kong for providing HEY and A278O cells (Shandong University, China). We also thank Dr Suneng Fu and Yilie Liao for their technical support on the extracellular acidification rate and oxygen consumption rate experiment. We thank Dr Suozhu Sun (The Second Artillery General Hospital, China) for his help with the pathological analyses on the tumor samples. This work was supported by Grants from Ministry of Science and Technology, China (2016YFA0500300, 2011CB910502 and 2011CB915504) and NSFC (81672715, 81301701, 81572729, 81402293 and 81230044) in China.

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Author notes

  1. Y Shang and J He: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Biology, The Key Laboratory for Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China

    Y Shang, J He, G Yan, Y Zhai & D He

  2. Department of Basic Medical Sciences, State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China

    Y Shang, Y Wang, Y Zhang, J Guo, J Li, S Li, Y Wang, F Ren & Z Chang

  3. Department of Gynecology and Obstetrics, The Third Affiliated Hospital, Zhengzhou University, Zhengzhou, China

    Q Feng

  4. Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, PA, USA

    Y Shi

  5. School of Pathology and Laboratory Medicine, The University of Western Australia (M504), Crawley, WA, Australia

    J Xu

  6. School of Surgery, The University of Western Australia (M509), Crawley, WA, Australia

    N Zeps

  7. St John of God HealthCare, The Bendat Family Comprehensive Cancer Centre, Subiaco, WA, Australia

    N Zeps

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Correspondence to Y Shang or Z Chang.

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Shang, Y., He, J., Wang, Y. et al. CHIP/Stub1 regulates the Warburg effect by promoting degradation of PKM2 in ovarian carcinoma. Oncogene 36, 4191–4200 (2017). https://doi.org/10.1038/onc.2017.31

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  • DOI: https://doi.org/10.1038/onc.2017.31

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