Editors' ChoiceCancer

Inhibiting HIF with Fructose-1,6-Bisphosphastase

Sci. Signal.  16 Sep 2014:
Vol. 7, Issue 343, pp. ec253
DOI: 10.1126/scisignal.2005899

When oxygen is limiting, cells adjust their metabolism through the transcription factors hypoxia-inducible factors (HIFs). Loss of function of VHL, a protein necessary to maintain the low abundance of HIFs under normoxic conditions, results in constitutively active HIFs and contributes to some forms of cancer, in particular clear cell renal carcinoma (ccRCC). Li et al. found through metabolomic analysis that primary human ccRCCs had higher glucose metabolism but lower gluconeogenesis than matched normal kidney tissue. The tumors universally had reduced or undetectable amounts of the enzyme fructose-1,6-bisphosphatase 1 (FBP1). Knockdown of endogenous FBP1 enhanced the proliferation of HK-2 cells, a proximal tubule cell line. Ectopic expression of FBP1 (to amounts similar to those in HK-2 cells) in a ccRCC line inhibited tumor growth when xenografted in mice and inhibited anchorage-dependent and anchorage-independent growth in culture. Ectopic expression of FBP1 in ccRCC cells reduced glycolysis and the amount of NADPH, effects that were suppressed by reintroduction of VHL, indicating that these effects of FBP1 depended on the aberrantly stabilized HIF proteins. Ectopic expression of FBP1 in ccRCC cells inhibited HIF transcriptional activity, and chromatin immunoprecipitation analysis of these cells showed that both HIF-1α and FBP1 were present on the HIF target gene promoters. Expression of an FBP1 point mutant that lacks catalytic activity, but not one with a nuclear export sequence, inhibited HIF target gene expression, reduced cell proliferation, and altered glucose metabolism. Coimmunoprecipitation and glutathione-S-transferase pull-down experiments with HIF proteins and FBP1 showed that a region in the N-terminal domain of FBP1 and the HIF inhibitory domain interacted. Thus, FBP1 functions as a tumor suppressor by inhibiting HIF activity to block protumorigenic changes in cellular metabolism.

B. Li, B. Qiu, D. S. M. Lee, Z. E. Walton, J. D. Ochocki, L. K. Mathew, A. Mancuso, T. P. F. Gade, B. Keith, I. Nissim, M. C. Simon, Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513, 251–255 (2014). [PubMed]