Journal of Neuro-Oncology

, Volume 130, Issue 1, pp 111–122 | Cite as

ZEB1 expression is increased in IDH1-mutant lower-grade gliomas

  • Cody L. Nesvick
  • Chao Zhang
  • Nancy A. Edwards
  • Blake K. Montgomery
  • Michaela Lee
  • Chunzhang Yang
  • Herui Wang
  • Dongwang Zhu
  • John D. Heiss
  • Marsha J. Merrill
  • Abhik Ray-Chaudhury
  • Zhengping Zhuang
Laboratory Investigation


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.


IDH 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.

Supplementary material

11060_2016_2240_MOESM1_ESM.doc (237 kb)
Supplementary material 1 (DOC 237 KB)


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Copyright information

© Springer Science+Business Media New York (outside the USA) 2016

Authors and Affiliations

  • Cody L. Nesvick
    • 1
    • 2
  • Chao Zhang
    • 1
  • Nancy A. Edwards
    • 1
  • Blake K. Montgomery
    • 1
    • 3
  • Michaela Lee
    • 1
    • 4
  • Chunzhang Yang
    • 1
    • 5
  • Herui Wang
    • 1
  • Dongwang Zhu
    • 1
  • John D. Heiss
    • 1
  • Marsha J. Merrill
    • 1
  • Abhik Ray-Chaudhury
    • 1
  • Zhengping Zhuang
    • 1
  1. 1.Surgical Neurology BranchNational Institutes of Neurological Disorders and StrokeBethesdaUSA
  2. 2.Department of Neurologic SurgeryMayo ClinicRochesterUSA
  3. 3.Department of Orthopaedic SurgeryStanford UniversityRedwood CityUSA
  4. 4.Department of Neurological SurgeryThe George Washington UniversityWashington, DCUSA
  5. 5.Neuro-Oncology BranchNational Cancer InstituteBethesdaUSA

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