title: E2F1 enhances glycolysis through suppressing Sirt6 transcription in cancer cells.
abstract: The fast proliferation of cancer cells requires reprogramming of its energy metabolism with aerobic glycolysis as a major energy source. Sirt6, a class III histone deacetylase, has been shown to down regulate glycolysis by inhibiting the expression of several key glycolytic genes. Based on the published study on the metabolic phenotype of E2F1 -/- mice and SIRT6 -/- mice, we hypothesize that E2F1 enhances glycolysis and inhibits the expression of Sirt6. Indeed, over-expressing of E2F1, but not its DNA binding deficient mutant, significantly enhanced glucose uptake and lactate production in bladder and prostate cancer cell lines. E2F1 over-expression also suppressed Sirt6 expression and function. Moreover, E2F1 directly bound to Sirt6 promoter and suppressed Sirt6 promoter activity under both normoxic and hypoxic culture conditions. E2F1 siRNA blocked the up-regulation of E2F1 under hypoxia, increased Sirt6 expression and decreased glycolysis compared to those of scrambled siRNA transected cells. Furthermore, HDAC1 deacetylated E2F1 and diminished its transcription suppression of Sirt6 promoter. Treatment with the HDAC inhibitor, trichostatin A (TSA), suppressed Sirt6 promoter activity with increased binding of acetylated E2F1 to Sirt6 promoter. Mutating the E2F1 binding site on the proximal Sirt6 promoter abolished the suppression of Sirt6 transcription by TSA. These data indicate a novel oncogenic role of E2F1, i.e. enhancing glycolysis by suppressing Sirt6 transcription.
authors: Department of Genitourinary Oncology and Department of Cancer Imaging and Metabolism, H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors: Minghui
authors: M
authors: Wu
authors: Department of Molecular Oncology, H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors: Edward
authors: E
authors: Seto
authors: Department of Genitourinary Oncology and Department of Cancer Imaging and Metabolism, H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors: Jingsong
authors: J
authors: Zhang
mesh_terms: D001665:Binding Sites; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D009154:Mutation; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D034622:RNA Interference; D015398:Signal Transduction; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D056572:Histone Deacetylase Inhibitors; D019344:Lactic Acid; C516592:SIRT6 protein, human; D037761:Sirtuins; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
keywords: E2F1; HDAC1; SIRT6; glycolysis; metabolism