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Fructose-1,6-bisphosphatase opposes renal carcinoma progression

Abstract

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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Figure 1: Integrative analyses reveal that FBP1 is ubiquitously depleted and exhibits tumour-suppressive functions in ccRCC.
Figure 2: FBP1 regulates glycolysis and NADPH levels.
Figure 3: FBP1 inhibits HIF activity in the nucleus.
Figure 4: FBP1 inhibits HIF independent of its enzymatic activity, through direct interaction with a HIF-α inhibitory domain.

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Acknowledgements

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.

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Contributions

B.L., I.N. and M.C.S. designed this study. B.L., B.Q., D.S.M.L., Z.E.W. and J.D.O. performed the experiments. B.L., L.K.M., A.M., T.P.F.G., I.N. and M.C.S. analysed data. B.L., I.N., B.K. and M.C.S. wrote the paper.

Corresponding author

Correspondence to M. Celeste Simon.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Pan-metabolomic analysis of ccRCC tumour and adjacent normal kidney tissues.

a, Heat map showing the relative concentration of 418 metabolites detected in 20 primary ccRCC tumours and adjacent normal kidneys. Metabolites were extracted from frozen tissue samples and analysed by the Thermo-Finnigan GC-MS and LC-MS/MS systems. Raw data of each metabolite was rescaled to set the median equal to 1. All metabolites were clustered according to their related pathways (based on KEGG) and then plotted as a heat map. b, Metabolic genes involved in carbohydrate storage differentially expressed in ccRCC tumour vs normal tissue. G6PC, glucose-6-phosphatase, catalytic subunit; PCK1, phosphoenolpyruvate carboxykinase 1; FBP1, fructose-1,6-bisphosphatase 1. c, Illustration of central carbon metabolism, including glycolysis, gluconeogenesis, pentose phosphate pathway, and the TCA cycle. Enzymes controlling glycolysis (HK, hexokinase; PFK, phosphofructokinase; PKM, pyruvate kinase type M) are highlighted in red, while enzymes controlling gluconeogenesis (G6P, glucose-6-phosphatase; FBP, fructose-1,6-bisphosphatase; PCK, phosphoenolpyruvate carboxykinase) are highlighted in green. F6P, fructose 6-phosphate; F-1,6-BP, fructose 1,6-bisphosphate; DHAP, dihydroxyacetone phosphate; GAP, glyceraldehyde 3-phosphate; R5P, ribose 5-phosphate; X5P, xylulose 5-phosphate; E4P, erythrose 4-phosphate; S7P, sedoheptulose 7-phosphate; PEP, phosphoenolpyruvate; Pyr, pyruvate; Ac-CoA, acetyl-CoA; Lac, lactate; Cit, citrate; αKG, α-ketoglutarate; Glu, glutamate; Suc, succinate; Fum, fumarate; Mal, malate; Oac, oxaloacetate; Asp, aspartate; G-SH, reduced glutathione.

Extended Data Figure 2 FBP1 protein expression is dramatically reduced in ccRCC tumours.

a, Quantification of the immunohistochemical (IHC) staining shown in Fig. 1b. b, Microscopic evaluation of IHC staining of two representative ccRCC tumour and adjacent normal kidney tissues, with FBP1 antibody (brown) and haematoxylin counterstain (blue). c, Quantification of IHC staining of additional 170 ccRCC tumours and 23 normal kidney tissues with FBP1 antibody. d, Immunohistochemistry staining of a representative liver tissue microarray with FBP1 antibody. T, hepatocellular carcinoma (HCC) tissues; N, normal liver tissues. e, Quantification of IHC staining of 80 HCC tumours and 18 normal liver tissues with FBP1 antibody. f, Western blot analysis of indicated proteins in RCC4 cells with or without HIF1-α inhibition. g, h, qRT–PCR of indicated genes (g) and western blot analysis of indicated proteins (h) in HK-2 cells cultured under normoxia (21% O2) or hypoxia (0.5% O2) with or without HIF-1α ablation. RT–PCR values represent mean ± s.d. (three technical replicates from a representative experiment). The hash symbol represents a significant increase over vector control. *P < 0.01; #P < 0.01.

Extended Data Figure 3 FBP1, but not PFKL, expression decreases in ccRCC tumours and correlates with tumour stages and patient prognosis.

a–c, IHC staining of the kidney tissue microarray as shown in Fig. 1b, with G6PC (a), PCK1 (b) and PFKL (c) antibodies. T, ccRCC tumour; N, adjacent normal kidney. Quantification of each staining is shown on the right. d, Normalized RNA-seq reads of PFKL in 69 normal kidneys and 480 ccRCC tumours grouped into stage I–IV by TCGA. e, Kaplan–Meier survival curve of 429 ccRCC patients enrolled in TCGA database. Patients were equally divided into two groups (top and bottom 50% PFKL expression) based on PFKL mRNA levels in their tumours.

Extended Data Figure 4 FBP1 expression affects cell proliferation.

a, Shown on the left is the western blot analysis of V5-tagged FBP1 and actin in vector control or V5-FBP1-expressing 786-O cells; on the right are protein levels of FBP1 and actin in HK-2 cells and 786-O cells with or without ectopic FBP1 expression. b, Anchorage-independent growth assay of vector control or V5-FBP1-expressing 786-O cells. c, Xenograft growth curves as performed in Fig. 1f. d, e, Low-serum growth curve of vector control or V5-FBP1-expressing RCC10 (d) and 769-P (e) cells. Western blot analyses confirming FBP1 expression are shown on the right. f, Growth of A549 lung cancer cells under normoxia (21% O2) or hypoxia (0.5% O2) cultured in low serum medium (1% FBS), with or without FBP1 expression. g, Protein levels of V5-FBP1 and actin in A549 lung cancer cells as indicated in f. h, Western blot analysis confirming the effect of FBP1 ablation in HK-2 cells. i, j, Growth curves of HK-2 cells with G6PC inhibition (i) or V5-PFKL expression (j), as compared to vector control cells in 1% serum medium. Western blot analyses of indicated proteins are shown on the right. All values represent mean ± s.d. (four technical replicates, from two independent experiments). *P < 0.01.

Extended Data Figure 5 FBP1 regulates glycolysis, glutamine metabolism, and pentose phosphate pathway (PPP) in renal cells.

a, b, Glucose uptake (a) and lactate secretion (b) in HK-2 cells with or without FBP1 inhibition, cultured in medium containing 1 mM glucose. c, Carbon fate map showing the isotopomer distribution of indicated metabolites derived from [1,2-13C]glucose. 13C atoms are depicted as filled circles. 13C atoms directly going through the glycolytic pathway are coloured in black, while 13C atoms going through the PPP and recycled back to glycolysis are coloured in red. d, Glutamine uptake in vector control or FBP1-expressing RCC10 cells. e, Carbon fate map showing the isotopomer distribution of indicated metabolites derived from [U-13C]glutamine. f, M4 isotopomer distribution of indicated metabolites in vector control or FBP1-expressing RCC10 cells, labelled with [U-13C]glutamine. % M4 enrichment represents the mole per cent excess of M4 species above natural abundance. g, Fold changes of PPP-related metabolites detected in ccRCC tumours vs adjacent normal kidney. Note that generation of reduced glutathione (G-SH) requires NADPH, a major reducing product of PPP. P value is calculated based on Welch’s paired t-test. q value is the estimation of false discovery rate in multiple testing. h, Relative NADPH levels in HK-2 cells with or without FBP1 inhibition. i, M1 and M2 isotopomer distribution of lactate in HK-2 cells with or without FBP1 inhibition. j, Calculated PPP flux (relative to vector control) in HK-2 cells with or without FBP1 inhibition. k–n, M1 and M2 isotopomer distribution of lactate (k) and calculated PPP flux (l) in vector control or FBP1-expressing RCC10 cells. Relative glucose 6-phosphate (G6P) levels in HK-2 cells with or without FBP1 ablation (m), and in vector control or FBP1-expressing RCC10 cells (n). o, Western blot analysis of indicated proteins in vector control or FBP1-expressing RCC10 and RCC10-VHL cells. Experiments were performed in triplicates. Values represent mean ± s.d. *P < 0.05.

Extended Data Figure 6 FBP1 inhibits HIF and pseudohypoxia in ccRCC tumour cells.

a, Western blot analysis of indicated proteins in HK-2, RCC4 and RCC10 cells. b, c, Oxygen consumption in vector control or FBP1-expressing RCC4 (b) and RCC10 (c) cells was measured using the MitoXpress dye as described in the Methods. Antimycin A (an inhibitor of mitochondrial respiration) was used as negative control. d, Carbon fate map showing the isotopomer distribution of indicated metabolites derived from [U-13C]glutamine. Filled circles indicate 13C carbons derived from [U-13C]glutamine, whereas open circles represent carbons derived from endogenous sources. Note that by the PCK or ME pathway, M4 malate generates M3 pyruvate, which re-enters the TCA cycle through the PDH flux (coloured in red) to produce M6 or M2 citrate. ME, malic enzyme; PDH, pyruvate dehydrogenase. e, M1-M6 isotopomer distribution of citrate in vector control or FBP1-expressing RCC10 cells, labelled with [U-13C]glutamine. f, The enrichment ratio of M6 or M2 citrate to M3 pyruvate in vector control or FBP1-expressing RCC10 cells, labelled with [U-13C]glutamine. Note that this ratio is an indication of PDH activity. g, HIF reporter activity in RCC10 cells transfected with vector or V5-tagged G6PC. Protein levels of expressed V5-G6PC are shown on the right. h, 480 ccRCC tumours from TCGA database were equally divided into two groups (top and bottom 50% G6PC expression) based on G6PC mRNA levels, and their relative HIF activities were quantified and plotted as described in the Methods. NS, not significant. i–k, qRT–PCR analysis of HIF target genes in vector control or FBP1-expressing RCC4 (i), hypoxic A549 (j), or normoxic RCC10-VHL (k) cells. Experiments were repeated twice. Values represent mean ± s.d. (technical triplicates from a representative experiment) *P < 0.05.

Extended Data Figure 7 Nuclear FBP1 co-localizes with HIF at HREs and inhibits HIF activity.

a, ChIP assays evaluating FBP1 chromatin binding to HREs in the PDK1, LDHA and VEGF promoters. b, ChIP-reChIP analysis examining the co-localization of HIF-1α and FBP1 at HREs in the GLUT1, PDK1, LDHA and VEGF promoters. c, FBP1 protein levels detected in cytosolic and nuclear fractions of human kidney tissue. HDAC1, a nuclear protein, and HSP90, a cytosolic protein, reflect the purity of respective subcellular fractionations. d, Immunofluorescent staining of human kidney tissue (interstitial region) with FBP1 antibody. Rabbit IgG was used as a negative control, and DAPI is a fluorescent nuclear dye. e, Western blot analysis of V5-tagged FBP1 or FBP1(NES) (FBP1 linked to a C-terminal nuclear export sequence) in the cytosolic and nuclear fractions of transfected RCC10 cells. f, qRT–PCR analysis of HIF target genes in vector control, FBP1 or FBP1(NES)-expressing RCC10 cells. g, h, Glucose uptake (g) and lactate secretion (h) in vector control, FBP1 or FBP1(NES)-expressing RCC10 cells. i, Models depicting the metabolic status of normal kidney proximal tubular epithelial cells (left), and VHL-deficient ccRCC tumour cells where FBP1 expression is inhibited (right). Error bars represent s.d. except in a and b, which indicate s.e.m. Error bars were calculated based on three technical replicates from a representative experiment, and experiments were repeated twice to confirm the results. Hash symbols represent significant de-repression of indicated signals relative to wild-type FBP1. *P < 0.05; #P < 0.05.

Extended Data Figure 8 FBP1 regulates glucose metabolism and HIF activity in a catalytic-activity-independent manner.

a, Protein levels of ectopically expressed V5-FBP1 and V5-FBP1(G260R) mutant in 293T and RCC10 cells. Actin was used as a loading control. b, FBP1 enzymatic activity in the 293T cell lysates as shown in a. c, Western blot analysis of V5-tagged proteins and actin in vector control 786-O and RCC10-VHL cells or cells ectopically expressing V5-FBP1 or V5-FBP1(G260R). d, Growth of vector control, FBP1 or FBP1(G260R)-expressing 786-O cells in 1% serum medium. e–h, Glucose uptake (e), lactate secretion (f), relative NADPH levels (g), and indicated HIF target gene expression (h) in vector control, FBP1 or FBP1(G260R)-expressing RCC10 cells. i, Growth of vector control, FBP1 or FBP1(G260R)-expressing RCC10-VHL cells in 1% serum medium. j–m, Glucose uptake (j), lactate secretion (k), relative NADPH levels (l), and indicated HIF target gene expression (m) in vector control, FBP1 or FBP1(G260R)-expressing RCC10-VHL cells. Experiments were repeated twice. Values represent mean ± s.d. (technical triplicates from a representative experiment). *P < 0.01.

Extended Data Figure 9 FBP1 N-terminus is essential for HIF inhibition.

a–d, Growth of vector control, FBP1 or FBP1(G260R)-expressing RCC10 (a) and 786-O (b) cells in medium containing 1 mM glucose. HIF reporter activity in vector control RCC4 (c) and 786-O (d) cells, or cells ectopically expressing FBP1, FBP1(G260R), FBP1 R domain, and FBP1 C domain. e, Western blot analysis of V5-tagged proteins and actin in vector control 293T cells or cells expressing V5-FBP1, V5-FBP1(G260R), and indicated V5-FBP1 exon truncations. A schematic representation of FBP1 exons is shown above both blots. Note that the FBP1 R domain is encoded by exons 1 to 4, while the C domain by exons 5 to 7. f, FBP1 enzymatic activity in 293T cells expressing indicated constructs as shown in e. g, HIF reporter activity in RCC10 cells expressing indicated constructs as shown in e. h, Lysates of 293T cells expressing V5-FBP1 and HA-HIF-1α (P402A/P564A double mutant) were immunoprecipitated with IgG or V5 antibody and blotted for HA. i, Lysates of RCC10 cells expressing V5-FBP1 were immunoprecipitated with IgG or V5 antibody and blotted for endogenous HIF-1α. Experiments were repeated twice. Values represent mean ± s.d. (technical triplicates from a representative experiment). Hash symbols represent significant de-repression of HIF reporter activity relative to wild-type FBP1. *P < 0.01; #P < 0.05.

Extended Data Figure 10 FBP1 directly interacts with HIF-α C-terminus.

a, Lysates of 293T cells ectopically expressing V5-FBP1 and HA-HIF-2α (P405A/P531A double mutant) were immunoprecipitated with IgG or V5 antibody and blotted for HA. b, Lysates of RCC10 cells expressing V5-FBP1 were immunoprecipitated with IgG or V5 antibody and blotted for endogenous HIF-2α. c, Lysates of 293T cells expressing V5-FBP1 and GFP, GFP-PHD2, or GFP-FIH1 were immunoprecipitated with or without V5 antibody and blotted for GFP. d, GST pull-down analysis between recombinant FBP1 and recombinant GST or GST-tagged HIF-2α. e, Schematic representation of HIF-α structural motifs. Note that in GAL4 transactivation assays, the HIF-α bHLH DNA-binding domain was replaced by a GAL4 DNA-binding domain (GBD). f, g, The ratio of GAL4 activity in the presence/absence of FBP1 (FBP1/vector), measured in cells expressing indicated HIF-1α (f) or HIF-2α (g) truncations in which the HIF bHLH DNA-binding domain was replaced by a GBD. Transfection efficiencies were normalized to co-expressed pRenilla-luciferase. Values represent mean ± s.d. (n = 3, technical replicates). Experiments were repeated twice.

Supplementary information

Supplementary Information

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). (PDF 159 kb)

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Li, B., Qiu, B., Lee, D. et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513, 251–255 (2014). https://doi.org/10.1038/nature13557

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