Isocitrate Dehydrogenase (IDH) Mutations Promote a Reversible ZEB1/MicroRNA (miR)-200-dependent Epithelial-Mesenchymal Transition (EMT)*
Autor: | Rob Howes, Thomas Henley, Joshua M. Korn, Alexandra R. Grassian, D P Gitterman, Julian Levell, Holly Astley, Fallon Lin, Yue Liu, Raymond Pagliarini, Rosemary Barrett, Manav Korpal, Wei Jiang |
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Jazyk: | angličtina |
Rok vydání: | 2012 |
Předmět: |
IDH1
Epithelial-Mesenchymal Transition Mutant Mutation Missense Biology medicine.disease_cause Biochemistry Gene Expression Regulation Enzymologic Glutarates Cell Line Tumor Neoplasms medicine Humans Epithelial–mesenchymal transition RNA Neoplasm Molecular Biology Regulation of gene expression Homeodomain Proteins Mutation Zinc Finger E-box-Binding Homeobox 1 Cell Biology Phenotype Isocitrate Dehydrogenase Neoplasm Proteins Up-Regulation Gene Expression Regulation Neoplastic MicroRNAs Isocitrate dehydrogenase Amino Acid Substitution Cancer research Carcinogenesis human activities Transcription Factors |
Popis: | 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. |
Databáze: | OpenAIRE |
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