Isocitrate Dehydrogenase (IDH) Mutations Promote a Reversible ZEB1/MicroRNA (miR)-200-dependent Epithelial-Mesenchymal Transition (EMT)

• Published in: The Journal of biological chemistry Vol. 287; no. 50; pp. 42180 - 42194
• Main Authors: Grassian, Alexandra R., Lin, Fallon, Barrett, Rosemary, Liu, Yue, Jiang, Wei, Korpal, Manav, Astley, Holly, Gitterman, Daniel, Henley, Thomas, Howes, Rob, Levell, Julian, Korn, Joshua M., Pagliarini, Raymond
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.12.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Substitution; Cancer Biology; Cell Biology; Cell Line, Tumor; Cell Metabolism; EMT; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glutarates - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Isocitrate Dehydrogenase - biosynthesis; Isocitrate Dehydrogenase - genetics; MicroRNAs - biosynthesis; MicroRNAs - genetics; Mutation, Missense; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Oncogene; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics; Signal Transduction; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Cell Biology; Tumor Metabolism; Up-Regulation - genetics; Zinc Finger E-box-Binding Homeobox 1; Tumor Metabolism; Tumor Cell Biology; Signal Transduction; Cell Metabolism; Oncogene; Cancer Biology; EMT
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.417832

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. Background: Isocitrate dehydrogenase (IDH) mutations occur in diverse tumor types, leading to production of the oncometabolite 2-hydroxyglutarate (2-HG). Results: High 2-HG levels lead to a reversible epithelial-mesenchymal transition (EMT) phenotype, which is dependent on ZEB1/miR-200. Conclusion: Mutant IDH reversibly disrupts normal epithelial morphology through EMT induction, a possible tumorigenic mechanism. Significance: This is the first report of a reversible mutant IDH-dependent signaling phenotype.