title: Acetylation mediated by the p300/CBP-associated factor determines cellular energy metabolic pathways in cancer.
abstract: Normal cells produce energy either through OXPHOS in the presence of oxygen or glycolysis in its absence. Cancer cells produce energy preferably through glycolysis even in the presence of oxygen, thereby, acquiring survival and proliferative advantages. Oncogenes and tumour suppressors control these metabolic pathways by regulating the expression of their target genes involved in these processes. During hypoxia, HIF-1 favours high glycolytic flux by upregulating glycolytic enzymes. Conversely, p53 inhibits glycolysis and increases OXPHOS expression through TIGAR and SCO2 gene expression, respectively. We hypothesise that the p300/CBP-associated factor (PCAF) as a common co-factor shared between p53 and HIF-1 plays an important role in the regulation of energy production by modulating SCO2 and TIGAR gene expression mediated by these two transcription factors. The possible involvement of HIF-1 in the regulation of SCO2 and TIGAR gene expression was investigated in cells with different p53 status in normoxia- and hypoxia-mimicking conditions. Putative hypoxia response elements (HREs) were identified in the regulatory region of SCO2 and TIGAR gene promoters. Chromatin immunoprecipitation experiments suggested that HIF-1 was recruited to the putative HREs present in the SCO2 and TIGAR promoters in a cell type-dependent manner. Transcriptional assays endorsed the notion that PCAF may be involved in the determination of the SCO2 and TIGAR cellular levels, thereby, regulating cellular energy metabolism, a view supported by assays measuring lactic acid production and oxygen consumption in cells ectopically expressing PCAF. The present study identified HIF-1 as a potential regulator of SCO2 and TIGAR gene expression. Furthermore, evidence to suggest that PCAF is involved in the regulation of cellular energy production pathways in hypoxia-mimicking conditions is presented. This effect of PCAF is exerted by orchestrating differential recruitment of HIF-1α and p53 to the promoter of TIGAR and/or SCO2 genes, thereby, tailoring physiological needs and environmental conditions to SCO2 and TIGAR gene expression.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Stopford Building, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Rajendran
authors.forename: Richa
authors.initials: R
authors.lastname: Garva
authors.forename: Hassan
authors.initials: H
authors.lastname: Ashour
authors.forename: Travis
authors.initials: T
authors.lastname: Leung
authors.forename: Ian
authors.initials: I
authors.lastname: Stratford
authors.forename: Marija
authors.initials: M
authors.lastname: Krstic-Demonacos
authors.forename: Constantinos
authors.initials: C
authors.lastname: Demonacos
mesh_terms: D000107:Acetylation; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D016158:Genes, p53; D006019:Glycolysis; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010744:Phosphoric Monoester Hydrolases; D011401:Promoter Regions, Genetic; D020218:Response Elements; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D051793:Hypoxia-Inducible Factor 1; D047908:Intracellular Signaling Peptides and Proteins; D019344:Lactic Acid; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D010744:Phosphoric Monoester Hydrolases; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C400285:SCO2 protein, human; C512708:TIGAR protein, human