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.
Highlights
Isocitrate dehydrogenase (IDH) mutations occur in diverse tumor types, leading to production of the oncometabolite 2-hydroxyglutarate (2-HG)
Heterozygous expression of the relevant mutant alleles was observed in all other clones at the mRNA level, and insertion of the mutations did not result in notable changes in total IDH1 or IDH2 protein expression
Despite the high prevalence of IDH1 and IDH2 mutations in a wide variety of cancers, the lack of isocitrate dehydrogenase 1 and 2 (IDH1/2) mutant cell line models has made it challenging to elucidate the function of these oncogenes in tumorigenesis and to confirm whether phenotypes induced by mutant IDH are reversible after their establishment
Summary
Isocitrate dehydrogenase (IDH) mutations occur in diverse tumor types, leading to production of the oncometabolite 2-hydroxyglutarate (2-HG). 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. We generated a panel of HCT116 colorectal cancer cells and MCF-10A mammary epithelial cells with endogenously expressed, heterozygous, and clinically relevant IDH1/2 mutations Our characterization of these cell lines suggests differences in the ability of these IDH1/2 mutations to produce 2-HG in cells, an observation that allowed for the separation of the effects of 2-HG from the IDH mutation. Our data demonstrate that mutant IDH1/2 can regulate specific signaling pathways that remain dependent on continued mutant IDH expression and provide insight into core pathways that may be deregulated in epithelial tumors that bear the IDH1/2 mutation
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