title: Lactate dehydrogenase A silencing in IDH mutant gliomas.
abstract: BACKGROUND
  Mutations of the isocitrate dehydrogenase 1 and 2 gene (IDH1/2) were initially thought to enhance cancer cell survival and proliferation by promoting the Warburg effect. However, recent experimental data have shown that production of 2-hydroxyglutarate by IDH mutant cells promotes hypoxia-inducible factor (HIF)1α degradation and, by doing so, may have unexpected metabolic effects.
  
  
  METHODS
  We used human glioma tissues and derived brain tumor stem cells (BTSCs) to study the expression of HIF1α target genes in IDH mutant ((mt)) and IDH wild-type ((wt)) tumors. Focusing thereafter on the major glycolytic enzyme, lactate dehydrogenase A (LDHA), we used standard molecular methods and pyrosequencing-based DNA methylation analysis to identify mechanisms by which LDHA expression was regulated in human gliomas.
  
  
  RESULTS
  We found that HIF1α-responsive genes, including many essential for glycolysis (SLC2A1, PDK1, LDHA, SLC16A3), were underexpressed in IDH(mt) gliomas and/or derived BTSCs. We then demonstrated that LDHA was silenced in IDH(mt) derived BTSCs, including those that did not retain the mutant IDH1 allele (mIDH(wt)), matched BTSC xenografts, and parental glioma tissues. Silencing of LDHA was associated with increased methylation of the LDHA promoter, as was ectopic expression of mutant IDH1 in immortalized human astrocytes. Furthermore, in a search of The Cancer Genome Atlas, we found low expression and high methylation of LDHA in IDH(mt) glioblastomas.
  
  
  CONCLUSIONS
  To our knowledge, this is the first demonstration of downregulation of LDHA in cancer. Although unexpected findings, silencing of LDHA and downregulation of several other glycolysis essential genes raise the intriguing possibility that IDH(mt) gliomas have limited glycolytic capacity, which may contribute to their slow growth and better prognosis.
authors.affiliation: Department of Clinical Neurosciences, Foothills Hospital, Calgary, Alberta, Canada (C.C., M.D.B., M.A.-N., J.A.C., S.W., J.G.C.); Department of Cell Biology and Anatomy, Health Research Innovation Centre, Calgary, Alberta, Canada (O.D.S., S.W., H.A.L.); Department of Pathology & Laboratory Medicine, Foothills Hospital, Calgary, Alberta, Canada (J.A.C.); Southern Alberta Cancer Research Institute, Health Research Innovation Centre, Calgary, Alberta, Canada (C.C., M.D.B., M.A.-N., J.A.C., S.W., H.A.L., J.G.C.); Hotchkiss Brain Institute, Health Research Innovation Centre, Calgary, Alberta, Canada (O.D.S., S.W., H.A.L.); Department of Radiology and Biomedical Imaging, San Francisco, California (M.M.C., S.M.R.); Brain Tumor Research Center, Department of Neurological Surgery, San Francisco, California (R.O.P).
authors.forename: Charles
authors.initials: C
authors.lastname: Chesnelong
authors.forename: Myriam M
authors.initials: MM
authors.lastname: Chaumeil
authors.forename: Michael D
authors.initials: MD
authors.lastname: Blough
authors.forename: Mohammad
authors.initials: M
authors.lastname: Al-Najjar
authors.forename: Owen D
authors.initials: OD
authors.lastname: Stechishin
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chan
authors.forename: Russell O
authors.initials: RO
authors.lastname: Pieper
authors.forename: Sabrina M
authors.initials: SM
authors.lastname: Ronen
authors.forename: Samuel
authors.initials: S
authors.lastname: Weiss
authors.forename: H Artee
authors.initials: HA
authors.lastname: Luchman
authors.forename: J Gregory
authors.initials: JG
authors.lastname: Cairncross
mesh_terms: D000818:Animals; D020295:Brain Stem Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005909:Glioblastoma / Q000235:genetics; D005910:Glioma / Q000235:genetics*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D007527:Isoenzymes / Q000235:genetics; D007770:L-Lactate Dehydrogenase / Q000235:genetics*; D000080864:Lactate Dehydrogenase 5; D051379:Mice; D009154:Mutation
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D007521:Isocitrate Dehydrogenase
keywords: IDH mutation; LDHA; gliomas; glycolysis; methylation