Letter | Published:

Fructose-1,6-bisphosphatase opposes renal carcinoma progression

Nature volume 513, pages 251255 (11 September 2014) | Download Citation

Abstract

Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer1, is characterized by elevated glycogen levels and fat deposition2. These consistent metabolic alterations are associated with normoxic stabilization of hypoxia-inducible factors (HIFs)3 secondary to von Hippel–Lindau (VHL) mutations that occur in over 90% of ccRCC tumours4. However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation5, suggesting that additional mechanisms are essential. Recent large-scale sequencing analyses revealed the loss of several chromatin remodelling enzymes in a subset of ccRCC (these included polybromo-1, SET domain containing 2 and BRCA1-associated protein-1, among others)6,7,8,9, indicating that epigenetic perturbations are probably important contributors to the natural history of this disease. Here we used an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis and determined that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1)10 is uniformly depleted in over six hundred ccRCC tumours examined. Notably, the human FBP1 locus resides on chromosome 9q22, the loss of which is associated with poor prognosis for ccRCC patients11. Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms. First, FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin12, thereby inhibiting a potential Warburg effect13,14. Second, in pVHL (the protein encoded by the VHL gene)-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis and the pentose phosphate pathway in a catalytic-activity-independent manner, by inhibiting nuclear HIF function via direct interaction with the HIF inhibitory domain. This unique dual function of the FBP1 protein explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumour suppressors that are not consistently mutated in all tumours6,7,15.

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References

  1. 1.

    , & Renal cell carcinoma. Lancet 373, 1119–1132 (2009)

  2. 2.

    & Misdiagnosis of clear cell renal cell carcinoma. Nature Rev. Urol. 8, 321–333 (2011)

  3. 3.

    , & HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nature Rev. Cancer 12, 9–22 (2012)

  4. 4.

    et al. Improved identification of von Hippel–Lindau gene alterations in clear cell renal tumors. Clin. Cancer Res. 14, 4726–4734 (2008)

  5. 5.

    , & Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Res. 66, 2576–2583 (2006)

  6. 6.

    et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nature Genet. 45, 860–867 (2013)

  7. 7.

    The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013)

  8. 8.

    et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010)

  9. 9.

    et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011)

  10. 10.

    Regulation of fructose-bisphosphatase activity. Adv. Enzymol. 54, 121–194 (1983)

  11. 11.

    et al. Genomic copy number alterations in clear cell renal carcinoma: associations with case characteristics and mechanisms of VHL gene inactivation. Oncogenesis 1, e14 (2012)

  12. 12.

    & Renal-cell carcinoma. N. Engl. J. Med. 353, 2477–2490 (2005)

  13. 13.

    , & Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009)

  14. 14.

    & Cellular metabolism and disease: what do metabolic outliers teach us? Cell 148, 1132–1144 (2012)

  15. 15.

    et al. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin. Cancer Res. 19, 3259–3267 (2013)

  16. 16.

    et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346–350 (2011)

  17. 17.

    , , & Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 24, 382–391 (2001)

  18. 18.

    et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2012)

  19. 19.

    Metabolism at a Glance 3rd edn (Blackwell, 2004)

  20. 20.

    , & Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell 40, 294–309 (2010)

  21. 21.

    , , & Identification of a signal for rapid export of proteins from the nucleus. Cell 82, 463–473 (1995)

  22. 22.

    et al. Fructose 1,6-bisphosphatase deficiency: enzyme and mutation analysis performed on calcitriol-stimulated monocytes with a note on long-term prognosis. J. Inherit. Metab. Dis. 33 (suppl. 3). 113–121 (2010)

  23. 23.

    , & Crystal structures of fructose 1,6-bisphosphatase: mechanism of catalysis and allosteric inhibition revealed in product complexes. Biochemistry 39, 8565–8574 (2000)

  24. 24.

    et al. Genetic and functional studies implicate HIF1α as a 14q kidney cancer suppressor gene. Cancer Discov. 1, 222–235 (2011)

  25. 25.

    , , , & Transactivation and inhibitory domains of hypoxia-inducible factor 1alpha. Modulation of transcriptional activity by oxygen tension. J. Biol. Chem. 272, 19253–19260 (1997)

  26. 26.

    et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012)

  27. 27.

    et al. Integrative genomic analyses of sporadic clear cell renal cell carcinoma define disease subtypes and potential new therapeutic targets. Cancer Res. 72, 112–121 (2012)

  28. 28.

    , , , & Genome-wide identification of hypoxia-inducible factor binding sites and target genes by a probabilistic model integrating transcription-profiling data and in silico binding site prediction. Nucleic Acids Res. 38, 2332–2345 (2010)

  29. 29.

    et al. Effects of a glucokinase activator on hepatic intermediary metabolism: study with 13C-isotopomer-based metabolomics. Biochem. J. 444, 537–551 (2012)

  30. 30.

    et al. Mass isotopomer study of the nonoxidative pathways of the pentose cycle with [1,2-13C2]glucose. Am. J. Physiol. 274, E843–E851 (1998)

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Acknowledgements

We thank Y. Daikhin, O. Horyn and Ilana Nissim for assistance with the isotopomer enrichment analysis in the Metabolomic Core facility, Children's Hospital of Philadelphia. We also thank J. Tobias for help with processing the TCGA RNA-sequencing data. This work was supported by the Howard Hughes Medical Institute, NIH Grant CA104838 to M.C.S. and DK053761 to I.N. M.C.S. is an Investigator of the Howard Hughes Medical Institute.

Author information

Affiliations

  1. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Bo Li
    • , Bo Qiu
    • , David S. M. Lee
    • , Zandra E. Walton
    • , Joshua D. Ochocki
    • , Lijoy K. Mathew
    • , Anthony Mancuso
    • , Brian Keith
    •  & M. Celeste Simon
  2. Howard Hughes Medical Institute, Philadelphia, Pennsylvania 19104, USA

    • David S. M. Lee
    • , Lijoy K. Mathew
    •  & M. Celeste Simon
  3. Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Zandra E. Walton
    • , Anthony Mancuso
    •  & Brian Keith
  4. Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Anthony Mancuso
    •  & Terence P. F. Gade
  5. Department of Pediatrics, Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Itzhak Nissim
  6. Division of Child Development and Metabolic Disease, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA

    • Itzhak Nissim
  7. Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • M. Celeste Simon

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Contributions

B.L., I.N. and M.C.S. designed this study. B.L., B.Q., D.S.M.L., Z.E.W. and J.D.O. performed the experiments. B.L., L.K.M., A.M., T.P.F.G., I.N. and M.C.S. analysed data. B.L., I.N., B.K. and M.C.S. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to M. Celeste Simon.

Extended data

Supplementary information

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  1. 1.

    Supplementary Information

    This file contains the Supplementary Discussion which further discusses the tumor-suppressive functions of FBP1 in ccRCC, the differences between FBP1 and PKM2 in regulating HIF activity and the potential interplay between FBP1 and oxygen/nutrient homeostasis in major gluconeogenic organs (liver and kidney).

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DOI

https://doi.org/10.1038/nature13557

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