Abstract
The mechanism of tumorigenesis associated with nicotinamide adenine dinucleotide phosphate (NADP+)-dependent isocitrate dehydrogenase 1 (IDH1) mutations in gliomas is not fully understood. Loss of catalytic activity leading to a decrease in α-ketoglutarate (αKG) and gain of novel catalytic activity leading to production of d-2-hydroxylglutarate (d-2-HG) are both found in IDH1-mutated glioma cells. Both the decrease of αKG and accumulation of d-2-HG inhibit the activity of multiple dioxygenases including prolyl hydroxylase domain-2 (PHD2), collagen prolyl-4-hydroxylase, histone demethylases, and the ten–eleven translocation (TET) family of 5-methylcytosine hydroxylases. Here we correlated the products of these dioxygenases after IDH1 gene mutations with tumorigenesis in human astroglioma samples. DNA sequencing was carried out for 253 astroglioma samples to identify IDH1 mutations. Immunohistochemistry analysis was employed to verify the levels of endostatin, dimethylated H3k79 (H3k79me2), and 5-hydroxymethylcytosine (5hmC) in these astroglioma samples. IDH1 mutations occurred frequently in low grades of astrocytoma. One case bearing both IDH1 and IDH2 mutations was identified. IDH1-mutated cases displayed more frontal lobe location and p53-positive immunostaining than wild-type cases. IDH1 mutations were associated with increased histone methylation and decreased 5hmC. By inhibiting endostatin expression, IDH1 mutations indirectly promoted angiogenesis in gliomas. All these changes were same in astroglioma at different malignancy grade. IDH1 mutations showed wide regulation of angiogenesis and genome-wide change of histone and DNA methylation, which were not suppressed as the malignancy level progressed, suggesting an early role of IDH1 mutations in astrocytoma tumorigenesis.
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Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812. doi:10.1126
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773. doi:10.1056/NEJMoa0808710
Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su SM, Sharp KA, Levine RL, Thompson CB (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17:225–234. doi:10.1016/jccr201001020
Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Seo SI, Lee JY, Yoo NJ, Lee SH (2009) Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer 125:353–355. doi:10.1002/ijc.24379
Hartong DT, Dange M, McGee TL, Berson EL, Dryja TP, Colman RF (2008) Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle. Nat Genet 40:1230–1234. doi:10.1038/ng.223
Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, Yu W, Li Z, Gong L, Peng Y, Ding J, Lei Q, Guan KL, Xiong Y (2009) Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 324:261–265. doi:10.1126/science.1170944
Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744. doi:10.1038/nature08617
Rzem R, Veiga-da-Cunha M, Noël G, Goffette S, Nassogne MC, Tabarki B, Schöller C, Marquardt T, Vikkula M, Van Schaftingen E (2004) A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria. Proc Natl Acad Sci U S A 101:16849–16854. doi:10.1073/pnas.0404840101
Topçu M, Jobard F, Halliez S, Coskun T, Yalçinkayal C, Gerceker FO, Wanders RJ, Prud’homme JF, Lathrop M, Ozguc M, Fischer J (2004) L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1. Hum Mol Genet 13:2803–2811. doi:10.1093/hmg/ddh300
Aghili M, Zahedi F, Rafiee E (2009) Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review. J Neurooncol 91:233–236. doi:10.1007/s11060-008-9706-2
Annunen P, Helaakoski T, Myllyharju J, Veijola J, Pihlajaniemi T, Kivirikko KI (1997) Cloning of the human prolyl 4-hydroxylase alpha subunit isoform alpha(II) and characterization of the type II enzyme tetramer. The alpha(I) and alpha(II) subunits do not form a mixed alpha(I)alpha(II) beta2 tetramer. J Biol Chem 272:17342–17348. doi:10.1074/jbc.272.28.17342
Falnes PØ, Johansen RF, Seeberg E (2002) AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli. Nature 419:178–182. doi:10.1038/nature01048
Hirsilä M, Koivunen P, Günzler V, Kivirikko KI, Myllyharju J (2003) Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J Biol Chem 278:30772–30780. doi:10.1074/jbc.M304982200
Hirsilä M, Koivunen P, Günzler V, Kivirikko KI, Myllyharju J (2004) Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J Biol Chem 279:9899–9904. doi:10.1074/jbc.M312254200
Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT, Liu LX, Jiang WQ, Liu J, Zhang JY, Wang B, Frye S, Zhang Y, Xu YH, Lei QY, Guan KL, Zhao SM, Xiong Y (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19:17–30. doi:10.1016/j.ccr.2010.12.014
Kivirikko KI, Myllylä R, Pihlajaniemi T (1989) Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with four cosubstrates and a multifunctional subunit. FASEB J 3:1609–1617. doi:10.1074/jbc.M312254200
O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285. doi:S0092-8674(00)81848-6
Krane SM (2008) The importance of proline residues in the structure, stability and susceptibility to proteolytic degradation of collagens. Amino Acids 35:703–710. doi:10.1007/s00726-008-0073-2
Klose RJ, Kallin EM, Zhang Y (2006) JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet 7:715–727. doi:10.1038/nrg1945
Krivtsov AV, Feng Z, Lemieux ME, Faber J, Vempati S, Sinha AU, Xia X, Jesneck J, Bracken AP, Silverman LB, Kutok JL, Kung AL, Armstrong SA (2008) H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell 14:355–368. doi:10.1016/j.ccr.2008.10.001
Suzuki MM, Bird A (2008) DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 9:465–476. doi:10.1038/nrg2341
Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116:597–602. doi:10.1007/s00401-008-0455-2
Lai A, Kharbanda S, Pope WB, Tran A, Solis OE, Peale F, Forrest WF, Pujara K, Carrillo JA, Pandita A, Ellingson BM, Bowers CW, Soriano RH, Schmidt NO, Mohan S, Yong WH, Seshagiri S, Modrusan Z, Jiang Z, Aldape KD, Mischel PS, Liau LM, Escovedo CJ, Chen W, Nghiemphu PL, James CD, Prados MD, Westphal M, Lamszus K, Cloughesy T, Phillips HS (2011) Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin. J Clin Oncol 29:4482–4490
Fischer I, Gagner JP, Law M, Newcomb EW, Zagzag D (2005) Angiogenesis in gliomas: biology and molecular pathophysiology. Brain Pathol 15:297–310
Morimoto T, Aoyagi M, Tamaki M, Yoshino Y, Hori H, Duan L, Yano T, Shibata M, Ohno K, Hirakawa K, Yamaguchi N (2002) Increased levels of tissue endostatin in human malignant gliomas. Clin Cancer Res 8:2933–2938 http://clincancerres.aacrjournals.org/content/8/9/2933.long
Sakurai T, Kudo M (2011) Signaling pathways governing tumor angiogenesis. Oncology 81:24–29. doi:10.1159/000333256
Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES (2006) A bivalent chromatin structure marks key developemtal genes in embryonic stem cells. Cell 125:315–326. doi:10.1016/j.cell.2006.02.041
Zhu JK, Active DNA (2009) Demethylation mediated by DNA glucosylases. Annu Rev Genet 43:143–166. doi:10.1146/annurev-genet-102108-134205
Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome intergrates intrinsic and environmental signals. Nat Genet suppl 33:245–254. http://dx.doi.org/10.1038/ng1089
Ooi SK, Bestor TH (2008) The colorful history of active DNA demethylation. Cell 133:1145–1148. doi:10.1016/j.cell.2008.06.009
Bonasio R, Tu S, Reinberg D (2010) Molecular dignals of epigenetic states. Science 330:612–616. doi:10.1126/science.1191078
Feng J, Fan G (2009) The roles of DNA methylation in the central nervous system and neuropsychiatric disorders. Int Rev Neurobiol 89:67–84. doi:10.1016/S0074-7742(09)89004-1
Acknowledgments
We thank Professor Xue Xiong for critical suggestions on the manuscript. This work was support by Chinese National Science Foundation grants (30500189), Shanghai Nature Science Foundation Grants (12ZR1403200).
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Liu, Y., Jiang, W., Liu, J. et al. IDH1 mutations inhibit multiple α-ketoglutarate-dependent dioxygenase activities in astroglioma. J Neurooncol 109, 253–260 (2012). https://doi.org/10.1007/s11060-012-0914-4
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DOI: https://doi.org/10.1007/s11060-012-0914-4