Loss of Fructose-1,6-Bisphosphatase 1 Is Critical for Renal Carcinoma

The most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC), is characterized by increased levels of glycogen and fat accumulation and mutations in the von Hippel-Lindau (VHL) gene, which result in stabilization of hypoxia-inducible factors (HIF) under normoxic conditions and promote aerobic glycolysis and tumorigenesis. Although VHL mutations are found in the majority of ccRCCs, Vhl deletion in the murine kidney fails to induce the ccRCC phenotype, suggesting that additional mechanisms contribute to tumorigenesis. To identify potential regulators of ccRCC progression, Li and colleagues analyzed the levels of multiple metabolites and metabolic genes in primary human ccRCC tumors. This pan-metabolomic analysis revealed suppression of gluconeogenesis in ccRCCs and uniform depletion of fructose-1,6-bisphosphatase 1 (FBP1), a rate limiting gluconeogenic enzyme, in ccRCC tumors, which was correlated with advanced tumor stage and poor prognosis. Ectopic FBP1 expression in ccRCC cells prevented tumor cell growth, indicative of a functional role in tumor suppression. FBP1-dependent inhibition oftumor growth was mediated in part via suppression of glycolytic flux in renal proximal tubule epithelial cells, which have been implicated as the ccRCC cell of origin. In addition, re-expression of wild-type FBP1 or enzymatically inactive FBP1 in VHL-deficient cells inhibited cell growth and decreased glycolysis, NADPH production, and pentose phosphate pathway flux in a HIF-dependent manner, suggestive of a nonenzymatic function of FBP1 in regulating HIF. Indeed, FBP1 directly inhibited the transcriptional activity of HIF1α and HIF2α in the nucleus via interaction of the N-terminal regulatory domain of FBP1 with the C-terminal HIF inhibitory domain. These data identify loss of FBP1 as an important step in ccRCC progression and define a dual role for FBP1 as a ccRCC tumor suppressor that regulates both glucose metabolism and the hypoxic response.

Li B, Qiu B, Lee DS, Walton ZE, Ochocki JD, Mathew LK, et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 2014 Jul 20 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.