title: Developmental profile and regulation of the glycolytic enzyme hexokinase 2 in normal brain and glioblastoma multiforme.
abstract: Highly proliferating cells, normal or transformed, undergo aerobic glycolysis whereby glucose is metabolized to lactate rather than by oxidative metabolism, even in the presence of oxygen. This metabolic adaptation provides a survival advantage and facilitates synthesis of biosynthetic precursors required for continued cellular proliferation. An important mediator of aerobic glycolysis is our demonstration that in malignant gliomas there is over-expression of the glycolytic enzyme hexokinase 2 (HK2), phosphorylating glucose as the first step of the glycolytic pathway. In contrast, normal brain preferentially expresses HK1 and undergoes oxidative glucose metabolism. In this study, we examine whether this switch in HK isoform also occurs in the developing embryo and central nervous system (CNS). Bioinformatic analysis of available microarray data, including that of The Cancer Genome Atlas, demonstrated a ~17% overlap in metabolic-related genes in blastocyst stage embryo and human GBM tissue, including upregulation of HK2 and downregulation of HK1. Quantitative RT-PCR on mouse brains isolated at different embryonic and postnatal development time-points demonstrated HK2 expression was highest in the early embryo, while HK1 expression increased with CNS maturation. The downstream glycolytic enzymes PKM2 and LDHA had similar temporal profiles as HK2. Expression of the HK2 isoform was due in part to epigenetic regulation of HK2. In support, adult normal human brain and the few human GBM cell lines with low HK2 expression had methylation of CpG islands within intron 1 of HK2. In contrast, developing human fetal brain and GBM tissue expressing HK2 demonstrated significantly lower percent methylation. Furthermore, treatment of GBM cells lacking HK2 with 5-aza-2-deoxycytidine restored HK2 transcript expression. Overall, our results demonstrate that proliferative states including the developing embryo and malignant gliomas, which rely on aerobic glycolysis, preferentially express the HK2 isoform, found to be regulated in part epigenetically.
authors: The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children Research Institute, University of Toronto, Toronto, 11-401E, 101 College Street, East Tower, Ontario, Canada, M5G 1L7.
authors: Amparo
authors: A
authors: Wolf
authors: Sameer
authors: S
authors: Agnihotri
authors: Diana
authors: D
authors: Munoz
authors: Abhijit
authors: A
authors: Guha
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology / Q000201:enzymology* / Q000254:growth & development*; D001923:Brain Chemistry / Q000235:genetics; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics*; D002460:Cell Line; D002490:Central Nervous System / Q000201:enzymology / Q000254:growth & development; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics*; D006593:Hexokinase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007438:Introns / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013447:Sulfites / Q000494:pharmacology
chemical_list: D007527:Isoenzymes; D013447:Sulfites; D006593:Hexokinase; C042345:hydrogen sulfite