Publication Date:
2014-07-22
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162811/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162811/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Bo -- Qiu, Bo -- Lee, David S M -- Walton, Zandra E -- Ochocki, Joshua D -- Mathew, Lijoy K -- Mancuso, Anthony -- Gade, Terence P F -- Keith, Brian -- Nissim, Itzhak -- Simon, M Celeste -- CA104838/CA/NCI NIH HHS/ -- DK053761/DK/NIDDK NIH HHS/ -- F30 CA177106/CA/NCI NIH HHS/ -- F32 CA192758/CA/NCI NIH HHS/ -- P01 CA104838/CA/NCI NIH HHS/ -- P30 CA016520/CA/NCI NIH HHS/ -- R01 DK053761/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Sep 11;513(7517):251-5. doi: 10.1038/nature13557. Epub 2014 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Howard Hughes Medical Institute, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Pediatrics, Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Division of Child Development and Metabolic Disease, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Howard Hughes Medical Institute, Philadelphia, Pennsylvania 19104, USA [3] Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043030" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Basic Helix-Loop-Helix Transcription Factors/metabolism
;
Carcinoma, Renal Cell/*enzymology/genetics/physiopathology
;
Cell Line
;
Cell Line, Tumor
;
Cell Proliferation
;
Disease Progression
;
Epithelial Cells/metabolism
;
Fructose-Bisphosphatase/chemistry/genetics/*metabolism
;
Glycolysis
;
Humans
;
Kidney Neoplasms/*enzymology/genetics/physiopathology
;
Models, Molecular
;
NADP/metabolism
;
Protein Structure, Tertiary
;
Swine
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
