title: Isocitrate dehydrogenase (IDH) mutations promote a reversible ZEB1/microRNA (miR)-200-dependent epithelial-mesenchymal transition (EMT).
abstract: Mutations in the genes encoding isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in a variety of tumor types, resulting in production of the proposed oncometabolite, 2-hydroxyglutarate (2-HG). How mutant IDH and 2-HG alter signaling pathways to promote cancer, however, remains unclear. Additionally, there exist relatively few cell lines with IDH mutations. To examine the effect of endogenous IDH mutations and 2-HG, we created a panel of isogenic epithelial cell lines with either wild-type IDH1/2 or clinically relevant IDH1/2 mutations. Differences were noted in the ability of IDH mutations to cause robust 2-HG accumulation. IDH1/2 mutants that produce high levels of 2-HG cause an epithelial-mesenchymal transition (EMT)-like phenotype, characterized by changes in EMT-related gene expression and cellular morphology. 2-HG is sufficient to recapitulate aspects of this phenotype in the absence of an IDH mutation. In the cells types examined, mutant IDH-induced EMT is dependent on up-regulation of the transcription factor ZEB1 and down-regulation of the miR-200 family of microRNAs. Furthermore, sustained knockdown of IDH1 in IDH1 R132H mutant cells is sufficient to reverse many characteristics of EMT, demonstrating that continued expression of mutant IDH is required to maintain this phenotype. These results suggest mutant IDH proteins can reversibly deregulate discrete signaling pathways that contribute to tumorigenesis.
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Grassian
authors.forename: Fallon
authors.initials: F
authors.lastname: Lin
authors.forename: Rosemary
authors.initials: R
authors.lastname: Barrett
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Manav
authors.initials: M
authors.lastname: Korpal
authors.forename: Holly
authors.initials: H
authors.lastname: Astley
authors.forename: Daniel
authors.initials: D
authors.lastname: Gitterman
authors.forename: Thomas
authors.initials: T
authors.lastname: Henley
authors.forename: Rob
authors.initials: R
authors.lastname: Howes
authors.forename: Julian
authors.initials: J
authors.lastname: Levell
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Korn
authors.forename: Raymond
authors.initials: R
authors.lastname: Pagliarini
mesh_terms: D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005977:Glutarates / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D005977:Glutarates; D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human