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  • 1
    Publication Date: 2013-04-06
    Description: The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1), which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen blocked, in a dose-dependent manner, the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near-complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant--but not IDH1-wild-type--glioma cells without appreciable changes in genome-wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985613/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985613/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rohle, Dan -- Popovici-Muller, Janeta -- Palaskas, Nicolaos -- Turcan, Sevin -- Grommes, Christian -- Campos, Carl -- Tsoi, Jennifer -- Clark, Owen -- Oldrini, Barbara -- Komisopoulou, Evangelia -- Kunii, Kaiko -- Pedraza, Alicia -- Schalm, Stefanie -- Silverman, Lee -- Miller, Alexandra -- Wang, Fang -- Yang, Hua -- Chen, Yue -- Kernytsky, Andrew -- Rosenblum, Marc K -- Liu, Wei -- Biller, Scott A -- Su, Shinsan M -- Brennan, Cameron W -- Chan, Timothy A -- Graeber, Thomas G -- Yen, Katharine E -- Mellinghoff, Ingo K -- 1R01NS080944-01/NS/NINDS NIH HHS/ -- R01 NS080944/NS/NINDS NIH HHS/ -- U54CA143798/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2013 May 3;340(6132):626-30. doi: 10.1126/science.1236062. Epub 2013 Apr 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23558169" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzeneacetamides/administration & dosage/*pharmacology/toxicity ; *Cell Differentiation/drug effects ; Cell Transformation, Neoplastic ; Enzyme Inhibitors/*pharmacology/toxicity ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; Glioma/drug therapy/*enzymology/genetics/*pathology ; Glutarates/metabolism ; Histones/metabolism ; Imidazoles/administration & dosage/*pharmacology/toxicity ; Isocitrate Dehydrogenase/*antagonists & inhibitors/chemistry/*genetics/metabolism ; Methylation ; Mice ; Mice, SCID ; Mutant Proteins/antagonists & inhibitors/chemistry/metabolism ; Protein Multimerization ; RNA Interference ; Xenograft Model Antitumor Assays
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2012-02-22
    Description: Both genome-wide genetic and epigenetic alterations are fundamentally important for the development of cancers, but the interdependence of these aberrations is poorly understood. Glioblastomas and other cancers with the CpG island methylator phenotype (CIMP) constitute a subset of tumours with extensive epigenomic aberrations and a distinct biology. Glioma CIMP (G-CIMP) is a powerful determinant of tumour pathogenicity, but the molecular basis of G-CIMP remains unresolved. Here we show that mutation of a single gene, isocitrate dehydrogenase 1 (IDH1), establishes G-CIMP by remodelling the methylome. This remodelling results in reorganization of the methylome and transcriptome. Examination of the epigenome of a large set of intermediate-grade gliomas demonstrates a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation. Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and reshapes the methylome in a fashion that mirrors the changes observed in G-CIMP-positive lower-grade gliomas. Furthermore, the epigenomic alterations resulting from mutant IDH1 activate key gene expression programs, characterize G-CIMP-positive proneural glioblastomas but not other glioblastomas, and are predictive of improved survival. Our findings demonstrate that IDH mutation is the molecular basis of CIMP in gliomas, provide a framework for understanding oncogenesis in these gliomas, and highlight the interplay between genomic and epigenomic changes in human cancers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351699/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351699/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Turcan, Sevin -- Rohle, Daniel -- Goenka, Anuj -- Walsh, Logan A -- Fang, Fang -- Yilmaz, Emrullah -- Campos, Carl -- Fabius, Armida W M -- Lu, Chao -- Ward, Patrick S -- Thompson, Craig B -- Kaufman, Andrew -- Guryanova, Olga -- Levine, Ross -- Heguy, Adriana -- Viale, Agnes -- Morris, Luc G T -- Huse, Jason T -- Mellinghoff, Ingo K -- Chan, Timothy A -- R01 CA154767/CA/NCI NIH HHS/ -- R01CA154767-01/CA/NCI NIH HHS/ -- U54 CA143798/CA/NCI NIH HHS/ -- U54-CA143798/CA/NCI NIH HHS/ -- England -- Nature. 2012 Feb 15;483(7390):479-83. doi: 10.1038/nature10866.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22343889" target="_blank"〉PubMed〈/a〉
    Keywords: Astrocytes/cytology/metabolism ; Cell Survival/genetics ; Cells, Cultured ; CpG Islands/genetics ; DNA Methylation/*genetics ; Epigenesis, Genetic ; Epigenomics ; Gene Expression Regulation ; Glioblastoma/genetics/pathology ; Glioma/*genetics/pathology ; HEK293 Cells ; Histones/metabolism ; Humans ; Isocitrate Dehydrogenase/*genetics/metabolism ; Metabolome/genetics ; Mutation/*genetics ; *Phenotype ; Tumor Cells, Cultured
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2012-02-22
    Description: Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from alpha-ketoglutarate. Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro. Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478770/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478770/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lu, Chao -- Ward, Patrick S -- Kapoor, Gurpreet S -- Rohle, Dan -- Turcan, Sevin -- Abdel-Wahab, Omar -- Edwards, Christopher R -- Khanin, Raya -- Figueroa, Maria E -- Melnick, Ari -- Wellen, Kathryn E -- O'Rourke, Donald M -- Berger, Shelley L -- Chan, Timothy A -- Levine, Ross L -- Mellinghoff, Ingo K -- Thompson, Craig B -- R01 CA078831/CA/NCI NIH HHS/ -- R01 CA105463/CA/NCI NIH HHS/ -- U54CA143798/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 15;483(7390):474-8. doi: 10.1038/nature10860.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22343901" target="_blank"〉PubMed〈/a〉
    Keywords: 3T3-L1 Cells ; Adipocytes/cytology/drug effects/metabolism ; Animals ; Astrocytes/cytology/drug effects ; Cell Differentiation/drug effects/*genetics ; Cell Line, Tumor ; Cell Lineage/genetics ; DNA Methylation/drug effects ; Enzyme Induction/drug effects ; Gene Expression Regulation/drug effects ; Glioma/enzymology/genetics/pathology ; Glutarates/metabolism/pharmacology ; HEK293 Cells ; Histones/*metabolism ; Humans ; Isocitrate Dehydrogenase/antagonists & inhibitors/*genetics/metabolism ; Jumonji Domain-Containing Histone Demethylases/antagonists & ; inhibitors/deficiency/genetics/metabolism ; Methylation/drug effects ; Mice ; Mutation/*genetics ; Neural Stem Cells/metabolism ; Promoter Regions, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Keywords: CANCER ; PRIMARY BRAIN-TUMORS ; GLIOBLASTOMA ; GLUTAMINE-METABOLISM ; INTEGRATED GENOMIC ANALYSIS ; ISOCITRATE DEHYDROGENASE 1 ; BRANCHED-CHAIN AMINOTRANSFERASE ; ALPHA-KETOGLUTARATE ; MUTANT IDH1 ; 2 MUTATIONS
    Abstract: Here we show that glioblastoma express high levels of branched-chain amino acid transaminase 1 (BCAT1), the enzyme that initiates the catabolism of branched-chain amino acids (BCAAs). Expression of BCAT1 was exclusive to tumors carrying wild-type isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and was highly correlated with methylation patterns in the BCAT1 promoter region. BCAT1 expression was dependent on the concentration of alpha-ketoglutarate substrate in glioma cell lines and could be suppressed by ectopic overexpression of mutant IDH1 in immortalized human astrocytes, providing a link between IDH1 function and BCAT1 expression. Suppression of BCAT1 in glioma cell lines blocked the excretion of glutamate and led to reduced proliferation and invasiveness in vitro, as well as significant decreases in tumor growth in a glioblastoma xenograft model. These findings suggest a central role for BCAT1 in glioma pathogenesis, making BCAT1 and BCAA metabolism attractive targets for the development of targeted therapeutic approaches to treat patients with glioblastoma.
    Type of Publication: Journal article published
    PubMed ID: 23793099
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