oxalomalic-acid and Glioma

IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as α-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce α-KG and accumulate an α-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.

Topics: 5-Methylcytosine; Amino Acid Substitution; Animals; Binding, Competitive; Biocatalysis; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Catalytic Domain; Cell Line, Tumor; Cytosine; Dioxygenases; DNA-Binding Proteins; Endostatins; F-Box Proteins; Gene Expression; Glioma; Glutarates; Histone Demethylases; Histones; Homeodomain Proteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Isocitrate Dehydrogenase; Jumonji Domain-Containing Histone Demethylases; Ketoglutaric Acids; Mixed Function Oxygenases; Models, Molecular; Oxalates; Oxidoreductases, N-Demethylating; Procollagen-Proline Dioxygenase; Proto-Oncogene Proteins

Heterozygous mutations in the gene encoding isocitrate dehydrogenase-1 (IDH1) occur in certain human brain tumors, but their mechanistic role in tumor development is unknown. We have shown that tumor-derived IDH1 mutations impair the enzyme's affinity for its substrate and dominantly inhibit wild-type IDH1 activity through the formation of catalytically inactive heterodimers. Forced expression of mutant IDH1 in cultured cells reduces formation of the enzyme product, alpha-ketoglutarate (alpha-KG), and increases the levels of hypoxia-inducible factor subunit HIF-1alpha, a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by alpha-KG. The rise in HIF-1alpha levels was reversible by an alpha-KG derivative. HIF-1alpha levels were higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation. Thus, IDH1 appears to function as a tumor suppressor that, when mutationally inactivated, contributes to tumorigenesis in part through induction of the HIF-1 pathway.

Topics: Adolescent; Adult; Aged; Astrocytoma; Biocatalysis; Brain Neoplasms; Cell Line; Child; Female; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Glioblastoma; Glioma; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Isocitrate Dehydrogenase; Ketoglutaric Acids; Male; Middle Aged; Mutant Proteins; Oligodendroglioma; Oxalates; Protein Multimerization