Isocitrate Dehydrogenase Mutations Promote a ZEB1/mir-200-dependent Epithelial Mesenchymal Transition
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Grassian, Alexandra, Lin, Fallon, Barrett, Rosemary, Liu, Yue, Jiang, Wei, Korpal, Manav, Levell, Julian, 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 |