title: 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 is essential for p53-null cancer cells.
abstract: The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) controls metabolic flux through allosteric regulation of glycolysis. Here we show that p53 regulates the expression of PFKFB4 and that p53-deficient cancer cells are highly dependent on the function of this enzyme. We found that p53 downregulates PFKFB4 expression by binding to its promoter and mediating transcriptional repression via histone deacetylases. Depletion of PFKFB4 from p53-deficient cancer cells increased levels of the allosteric regulator fructose-2,6-bisphosphate, leading to increased glycolytic activity but decreased routing of metabolites through the oxidative arm of the pentose-phosphate pathway. PFKFB4 was also required to support the synthesis and regeneration of nicotinamide adenine dinucleotide phosphate (NADPH) in p53-deficient cancer cells. Moreover, depletion of PFKFB4-attenuated cellular biosynthetic activity and resulted in the accumulation of reactive oxygen species and cell death in the absence of p53. Finally, silencing of PFKFB4-induced apoptosis in p53-deficient cancer cells in vivo and interfered with tumour growth. These results demonstrate that PFKFB4 is essential to support anabolic metabolism in p53-deficient cancer cells and suggest that inhibition of PFKFB4 could be an effective strategy for cancer treatment.
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, London, UK.|Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ros
authors.affiliation: Theodor-Boveri-Institute, Biocenter, Am Hubland, Würzburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Flöter
authors.affiliation: Theodor-Boveri-Institute, Biocenter, Am Hubland, Würzburg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Kaymak
authors.affiliation: Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Da Costa
authors.affiliation: Protein Phosphorylation Unit, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Houddane
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Dubuis
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, London, UK.
authors.forename: B
authors.initials: B
authors.lastname: Griffiths
authors.affiliation: Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Mitter
authors.affiliation: Comprehensive Cancer Center, Core Unit Bioinformatics, Biocenter, Würzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Walz
authors.affiliation: Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Blake
authors.affiliation: Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK.|Faculty of Life Sciences and Medicine, King's College London, Guy's Campus, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Behrens
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: K M
authors.initials: KM
authors.lastname: Brindle
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Zamboni
authors.affiliation: Protein Phosphorylation Unit, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: M H
authors.initials: MH
authors.lastname: Rider
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, London, UK.|Theodor-Boveri-Institute, Biocenter, Am Hubland, Würzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schulze
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005632:Fructose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010084:Oxidation-Reduction; D010427:Pentose Phosphate Pathway; D025481:Phosphofructokinase-2 / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C506672:PFKFB4 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005632:Fructose; D025481:Phosphofructokinase-2; D005947:Glucose