Summary The MYC oncogene encodes a transcription factor, MYC, whose broad effects make its precise oncogenic role enigmatically elusive. The evidence to date suggests that MYC triggers selective gene expression amplification to promote cell growth and proliferation. Through its targets, MYC coordinates nutrient acquisition to produce ATP and key cellular building blocks that increase cell mass and trigger DNA replication and cell division. In cancer, genetic and epigenetic derangements silence checkpoints and unleash MYC’s cell growth- and proliferation-promoting metabolic activities. Unbridled growth in response to deregulated MYC expression creates dependence on MYC-driven metabolic pathways, such that reliance on specific metabolic enzymes provides novel targets for cancer therapy.

Clear cell renal cell carcinoma (ccRCC), the most frequent form of kidney cancer1, is characterized by elevated glycogen 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 loss of several chromatin remodelling enzymes in a subset of ccRCC (polybromo 1 [PBRM1] ~40%, SET domain containing 2 [SETD2] ~15%, BRCA1 associated protein-1 [BAP1] ~15%, etc.)6–9, indicating that epigenetic perturbations are likely important contributors to the natural history of this disease. Here we utilized 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. Importantly, the human FBP1 locus resides on chromosome 9q22, whose loss is associated with poor prognosis for ccRCC patients11. Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms: 1) FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin12, thereby inhibiting a potential “Warburg effect”13,14, and 2) in pVHL-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 (PBRM1, SETD2, BAP1, etc.) which are not consistently mutated in all tumours6,7,15.