ZEB1 expression is increased in IDH1-mutant lower-grade gliomas
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Transcription factors that induce epithelial-mesenchymal transition (EMT) promote invasion, chemoresistance and a stem-cell phenotype in epithelial tumors, but their roles in central nervous system tumors are not well-understood. We hypothesized these transcription factors have a functional impact in grades II–III gliomas. Using the National Cancer Institute (NCI) Repository for Molecular Brain Neoplasia Data (REMBRANDT) and the Cancer Genome Atlas (TCGA) Lower-Grade Glioma (LGG) data, we determined the impact of EMT-promoting transcription factors (EMT-TFs) on overall survival in grades II–III gliomas, compared their expression across common genetic subtypes and subsequently validated these findings in a set of 31 tumors using quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry. Increased expression of the gene coding for the transcriptional repressor Zinc Finger E box-binding Homeobox 1 (ZEB1) was associated with a significant increase in overall survival (OS) on Kaplan–Meier analysis. Genetic subtype analysis revealed that ZEB1 expression was relatively increased in IDH1/2-mutant gliomas, and IDH1/2-mutant gliomas expressed significantly lower levels of many ZEB1 transcriptional targets. Similarly, IDH1/2-mutant tumors expressed significantly higher levels of targets of microRNA 200C (MIR200C), a key regulator of ZEB1. In a validation study, ZEB1 mRNA was significantly increased in IDH1-mutant grades II–III gliomas, and ZEB1 protein expression was more pronounced in these tumors. Our findings demonstrate a novel relationship between IDH1/2 mutations and expression of ZEB1 and its transcriptional targets. Therapy targeting ZEB1-associated pathways may represent a novel therapeutic avenue for this class of tumors.
KeywordsIDH Lower-grade glioma Epithelial-mesenchymal transition ZEB1
The authors wish to thank Ms. Barbara Ikejiri for her extensive assistance in the preparation of materials used in experiments conducted in this study. The authors also wish to thank Dr. Lynn Young of the NIH Library Bioinformatics Support Program for her guidance in the gene expression analyses performed in this study. This research was supported by the Intramural Research Program at the National Institute of Neurological Disorders and Stroke and the National Institutes of Health (NIH) Medical Research Scholars Program, a public–private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer, Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc. and Mr. and Mrs. Joel S. Marcus and the Howard Hughes Medical Institute, as well as other private donors. Funding sources had no role in study design; data collection, analysis or interpretation; writing of the manuscript; or decision to submit this material for publication.
This research was supported by the Intramural Research Program at the National Institute of Neurological Disorders and Stroke and the National Institutes of Health Medical Research Scholars Program.
Compliance with ethical standards
Conflict of interest
The authors have no known conflicts of interest to declare.
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