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Isocitrate Dehydrogenase Mutations Promote a ZEB1/mir-200-dependent Epithelial Mesenchymal Transition

Grassian, Alexandra and Lin, Fallon and Barrett, Rosemary and Liu, Yue and Jiang, Wei and Korpal, Manav and Levell, Julian and Korn, Joshua and Pagliarini, Raymond (2012) Isocitrate Dehydrogenase Mutations Promote a ZEB1/mir-200-dependent Epithelial Mesenchymal Transition. Journal of Biological Chemistry, 287 (50). pp. 42180-42194. ISSN 0021-9258

Abstract

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in a variety of tumor types, and these mutations result in production of the oncometabolite, 2-hydroxyglutarate (2-HG). However it is not clear how mutant IDH and 2-HG alter signaling to promote cancer.To address this question, we created a panel of isogenic IDH1/2 wild-type and mutant colon carcinoma and mammary epithelial cell lines. From this, differences were noted in the ability of different IDH2 mutations to cause robust 2-HG accumulation. We find that IDH1/2 mutants producing high levels of intracellular 2-HG cause an epithelial mesenchymal transition (EMT)-like phenotype, characterized by changes in EMT-related gene expression as well as changes in cellular morphology. Addition of exogenous 2-HG to an IDH wild-type cell line is sufficient on its own to induce an EMT-like phenotype. The mutant IDH-induced EMT is dependent on upregulation of the transcription factor ZEB1 and downregulation of the mir-200 family of micro RNA’s. Knockdown of IDH1 in IDH1 R132H mutant cells is sufficient to reverse the EMT-like phenotype, demonstrating the necessity for continued expression of mutant IDH and 2-HG to maintain this phenotype. These results suggest mutant IDH proteins reversibly deregulate discreet signaling pathways that contribute to tumorigenesis.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/8251

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