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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Protein Data Bank
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.
Extended data figures
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).