Skip to main content

Advertisement

SpringerLink
Log in

A novel VHLα isoform inhibits Warburg effect via modulation of PKM splicing

  • Original Article
  • Published:
Tumor Biology

Abstract

Von Hippel-Lindau (VHL) is the most frequently mutated gene in clear cell renal carcinoma. Here, we identified a novel translational variant of VHL, termed VHLα, initiated from an alternative translational start site upstream and in frame with the ATG start codon. We showed that VHLα interacts with and regulates heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), which consequently modulates pyruvate kinase transcript splicing and reprograms cellular glucose metabolism. Our study demonstrated that a novel VHL isoform may function as a tumor suppressor through inhibiting the Warburg effect.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, Latif F, Liu S, Chen F, Duh FM, et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994;7:85–90.

    Article  CAS  PubMed  Google Scholar 

  2. Tory K, Brauch H, Linehan M, Barba D, Oldfield E, Filling-Katz M, Seizinger B, Nakamura Y, White R, Marshall FF, et al. Specific genetic change in tumors associated with von Hippel-Lindau disease. J Natl Cancer Inst. 1989;81:1097–101.

    Article  CAS  PubMed  Google Scholar 

  3. Kurban G, Hudon V, Duplan E, Ohh M, Pause A. Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis. Cancer Res. 2006;66:1313–9.

    Article  CAS  PubMed  Google Scholar 

  4. Schermer B, Ghenoiu C, Bartram M, Muller RU, Kotsis F, Hohne M, Kuhn W, Rapka M, Nitschke R, Zentgraf H, Fliegauf M, Omran H, Walz G, Benzing T. The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth. J Cell Biol. 2006;175:547–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Esteban MA, Harten SK, Tran MG, Maxwell PH. Formation of primary cilia in the renal epithelium is regulated by the von Hippel-Lindau tumor suppressor protein. J Am Soc Nephrol. 2006;17:1801–6.

    Article  CAS  PubMed  Google Scholar 

  6. Lutz MS, Burk RD. Primary cilium formation requires von Hippel-Lindau gene function in renal-derived cells. Cancer Res. 2006;66:6903–7.

    Article  CAS  PubMed  Google Scholar 

  7. Thoma CR, Frew IJ, Krek W. The VHL tumor suppressor: riding tandem with GSK3beta in primary cilium maintenance. Cell Cycle. 2007;6:1809–13.

    Article  CAS  PubMed  Google Scholar 

  8. Roe JS, Kim H, Lee SM, Kim ST, Cho EJ, Youn HD. P53 stabilization and transactivation by a von Hippel-Lindau protein. Mol Cell. 2006;22:395–405.

    Article  CAS  PubMed  Google Scholar 

  9. Young AP, Schlisio S, Minamishima YA, Zhang Q, Li L, Grisanzio C, Signoretti S, WG Jr K. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nat Cell Biol. 2008;10:361–9.

    Article  CAS  PubMed  Google Scholar 

  10. Blankenship C, Naglich JG, Whaley JM, Seizinger B, Kley N. Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity. Oncogene. 1999;18:1529–35.

    Article  CAS  PubMed  Google Scholar 

  11. Iliopoulos O, Ohh M, WG Jr K. pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation. Proc Natl Acad Sci U S A. 1998;95:11661–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schoenfeld A, Davidowitz EJ, Burk RD. A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor. Proc Natl Acad Sci U S A. 1998;95:8817–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Duan DR, Pause A, Burgess WH, Aso T, Chen DY, Garrett KP, Conaway RC, Conaway JW, Linehan WM, Klausner RD. Inhibition of transcription elongation by the VHL tumor suppressor protein. Science. 1995;269:1402–6.

    Article  CAS  PubMed  Google Scholar 

  14. Kibel A, Iliopoulos O, DeCaprio JA, WG Jr K. Binding of the von Hippel-Lindau tumor suppressor protein to elongin b and c. Science. 1995;269:1444–6.

    Article  CAS  PubMed  Google Scholar 

  15. Kishida T, Stackhouse TM, Chen F, Lerman MI, Zbar B. Cellular proteins that bind the von Hippel-Lindau disease gene product: mapping of binding domains and the effect of missense mutations. Cancer Res. 1995;55:4544–8.

    CAS  PubMed  Google Scholar 

  16. Feldman DE, Thulasiraman V, Ferreyra RG, Frydman J. Formation of the VHL-elongin BC tumor suppressor complex is mediated by the chaperonin TRiC. Mol Cell. 1999;4:1051–61.

    Article  CAS  PubMed  Google Scholar 

  17. Lonergan KM, Iliopoulos O, Ohh M, Kamura T, Conaway RC, Conaway JW, Kaelin WG. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Mol Cell Biol. 1998;18:732–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kamura T, Koepp DM, Conrad MN, Skowyra D, Moreland RJ, Iliopoulos O, Lane WS, WG Jr K, Elledge SJ, Conaway RC, Harper JW, Conaway JW. Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science. 1999;284:657–61.

    Article  CAS  PubMed  Google Scholar 

  19. Pause A, Lee S, Worrell RA, Chen DY, Burgess WH, Linehan WM, Klausner RD. The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc Natl Acad Sci U S A. 1997;94:2156–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271–5.

    Article  CAS  PubMed  Google Scholar 

  21. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294:1337–40.

    Article  CAS  PubMed  Google Scholar 

  22. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, WG Jr K. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464–8.

    Article  CAS  PubMed  Google Scholar 

  23. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292:468–72.

    Article  CAS  PubMed  Google Scholar 

  24. Yu F, White SB, Zhao Q, Lee FS. HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci U S A. 2001;98:9630–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW. Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci U S A. 2000;97:10430–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33:207–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gnarra JR, Zhou S, Merrill MJ, Wagner JR, Krumm A, Papavassiliou E, Oldfield EH, Klausner RD, Linehan WM. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci U S A. 1996;93:10589–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Esteban MA, Maxwell PH. HIF, a missing link between metabolism and cancer. Nat Med. 2005;11:1047–8.

    Article  CAS  PubMed  Google Scholar 

  29. Sendoel A, Kohler I, Fellmann C, Lowe SW, Hengartner MO. HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase. Nature. 2010;465:577–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cai Q, Verma SC, Kumar P, Ma M, Erle S. Robertson: hypoxia inactivates the VHL tumor suppressor through PIASy-mediated SUMO modification. PLoS One. 2010;5:e9720.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Starck SR, Jiang V, Pavon-Eternod M, Prasad S, McCarthy B, Pan T, Shastri N. Leucine-tRNA initiates at CUG start codons for protein synthesis and presentation by MHC class I. Science. 2012;336:1719–23.

    Article  CAS  PubMed  Google Scholar 

  32. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013;8:2281–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Krecic AM, Swanson MS. hnRNP complexes: composition, structure, and function. Curr Opin Cell Biol. 1999;11:363–71.

    Article  CAS  PubMed  Google Scholar 

  34. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452:230–3.

    Article  CAS  PubMed  Google Scholar 

  35. Kozak M. At least six nucleotides preceding the AUG initiator codon enhance translation in mammalian cells. J Mol Biol. 1987;196:947–50.

    Article  CAS  PubMed  Google Scholar 

  36. Kozak M. Initiation of translation in prokaryotes and eukaryotes. Gene. 1999;234:187–208.

    Article  CAS  PubMed  Google Scholar 

  37. Hann SR, King MW, Bentley DL, Anderson CW, Eisenman RN. A non-AUG translational initiation in c-myc exon 1 generates an n-terminally distinct protein whose synthesis is disrupted in Burkitt’s lyphomas. Cell. 1988;52.

  38. Gerashchenko MV, Su D, Gladyshev VN. CUG start codon generates thioredoxin/glutathione reductase isoforms in mouse testes. J Biol Chem. 2010;285.

  39. Malarkannan S, Horng T, Shih PP, Schwab S, Shastri N. Presentation of out-of-frame peptide/MHC class I complexes by a novel translation initiation mechanism. Immunity. 1999;10.

  40. Linehan WM, Srinivasan R, Schmidt LS. The genetic basis of kidney cancer: a metabolic disease. Nat Rev Urol. 2010;7:277–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nilsson H, Lindgren D, Mandahl Forsberg A, Mulder H, Axelson H, Johansson ME. Primary clear cell renal carcinoma cells display minimal mitochondrial respiratory capacity resulting in pronounced sensitivity to glycolytic inhibition by 3-bromopyruvate. Cell Death Dis. 2015;6:e1585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. David CJ, Chen M, Assanah M, Canoll P, Manley JL. hnRNP proteins controlled by c-myc deregulate pyruvate kinase mRNA splicing in cancer. Nature. 2010;463:364–8.

    Article  CAS  PubMed  Google Scholar 

  43. Tan R, Frankel AD. Structural variety of arginine-rich RNA-binding peptides. Proc Natl Acad Sci U S A. 1995;92:5282–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported by a Natural Science Foundation of China grant (81472606) and the National Research Program of China (973 Program, 2011CB812400).

Author information

Authors and Affiliations

  1. Collaborative Innovation Center of Cancer Medicine, National Institute of Biological Sciences, Beijing, Beijing, 102206, China

    Yanbin Liu & Liang Chen

  2. National Institute of Biological Sciences, Beijing, Beijing, 102206, China

    Haixia Yang, Lin Li, She Chen & Feifei Zuo

Authors
  1. Yanbin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haixia Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. She Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Feifei Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Liang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yanbin Liu or Liang Chen.

Ethics declarations

Author contributions

YBL: conception and design, acquisition of data, analysis and interpretation of data, and drafting the manuscript; HXY and FFZ: acquisition of data; LL and SC: acquisition of data and analysis and interpretation of data; and LC: conception and design, analysis and interpretation of data, and drafting the manuscript.

Conflicts of interest

None.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Y., Yang, H., Li, L. et al. A novel VHLα isoform inhibits Warburg effect via modulation of PKM splicing. Tumor Biol. 37, 13649–13657 (2016). https://doi.org/10.1007/s13277-016-5191-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5191-y

Keywords

Search

Navigation