Fructose-1,6-bisphosphatase opposes renal carcinoma progression

Abstract

Fructose-1,6-bisphosphatase is shown to be depleted in clear cell renal cell carcinoma (ccRCC) and inhibits ccRCC progression by antagonizing glycolytic flux in renal tubular epithelial cells and by restraining cell proliferation, glycolysis, and the pentose phosphate pathway in von Hippel–Lindau-protein-deficient ccRCC cells by blocking hypoxia-inducible factor function. von Hippel–Lindau mutations occur in the vast majority of clear cell renal cell carcinoma (ccRCC) tumours, and these mutations result in stabilization of hypoxia-inducible factors. But this is not sufficient to cause the typical metabolic alterations found in ccRCC, nor sufficient for tumour formation. This paper reports that fructose-1,6-bisphosphatase (FBP1) was uniformly depleted in all of more than six hundred ccRCC tumours examined. FBP1 is shown to inhibit renal carcinoma progression through two different mechanisms. First, the enzyme antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin, and this inhibits any potential 'Warburg effect'. Second, FBP1 restrains cell proliferation, glycolysis and the pentose phosphate pathway in ccRCC cells deficient in the von Hippel–Lindau protein (pVHL) by blocking nuclear hypoxia-inducible factor function. 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.