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Fructose-1,6-bisphosphatase opposes renal carcinoma progression
Open accessAbstract
Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is characterized by elevated glycogen levels and fat deposition. These consistent metabolic alterations are associated with normoxic stabilization of hypoxia-inducible factors (HIFs) secondary to von Hippel-Lindau (VHL) mutations that occur in over 90% of ccRCC tumours. However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation, 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), 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) 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 patients. 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 origin, thereby inhibiting a potential Warburg effect. 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 tumours.
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“Hypoxia can provide energy to tumor cells by activating transcriptional programs that induce glucose uptake and glycolysis.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [47]
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Metadata
- Authors
- Li, B., Qiu, B., Lee, D. S. M., Walton, Z. E., Ochocki, J. D., Mathew, L. K., Mancuso, A., Gade, T. P. F., Keith, B., Nissim, I., & Simon, M. C.
- Affiliations
- Abramson Cancer Center (US)
- Howard Hughes Medical Institute (US)
- University of Pennsylvania (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Simon, M. Celeste
- ORCID
- Venue
- Nature
- Published
- 2014-07-20
- Volume
- 513
- Issue
- 7517
- Pages
- 251-255
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4162811
- OpenAlex
- W2069663698
- Cited by
- 535
- References
- 31
- Citations by year
- 2026: 24 · 2025: 38 · 2024: 44 · 2023: 44 · 2022: 48 · 2021: 64 · 2020: 54 · 2019: 42 · 2018: 54 · 2017: 42 · 2016: 40 · 2015: 33 · 2014: 6
- FWCI
- 12.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Cancer Institute (F30CA177106, P01CA104838, CA104838, F32CA192758, P30CA016520)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK053761, DK-053761, R56DK053761)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Renal cell carcinoma treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- FBP1, clear cell renal cell carcinoma, von Hippel-Lindau protein, hypoxia-inducible factor, glycolysis, pentose phosphate pathway, Warburg effect, renal tubular epithelial cells, tumor progression, chromatin remodeling, cancer metabolism, epigenetic regulation, gluconeogenesis
- MeSH terms
- Animals, Carcinoma, Renal Cell, Cell Line, Epithelial Cells, Glycolysis, Fructose-Bisphosphatase, Humans, Kidney Neoplasms, Models, Molecular, NADP, Swine, Protein Structure, Tertiary, Disease Progression, Cell Line, Tumor, Cell Proliferation, Basic Helix-Loop-Helix Proteins
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