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.
- 8.Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Liang Y, Diehn M, Watson N, Bollen AW, Aldape KD, Nicholas MK, Lamborn KR, Berger MS, Botstein D, Brown PO et al (2005) Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme. Proc Natl Acad Sci USA 102:5814–5819CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Liu XY, Gerges N, Korshunov A, Sabha N, Khuong-Quang DA, Fontebasso AM, Fleming A, Hadjadj D, Schwartzentruber J, Majewski J et al (2012) Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations. Acta Neuropathol (Berl) 124:615–625CrossRefGoogle Scholar
- 34.Grassian AR, Lin F, Barrett R, Liu Y, Jiang W, Korpal M, Astley H, Gitterman D, Henley T, Howes R et al (2012) Isocitrate dehydrogenase (IDH) mutations promote a reversible ZEB1/microRNA (miR)-200-dependent epithelial-mesenchymal transition (EMT). J Biol Chem 287:42180–42194CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M, Mikulits W, Brabletz T, Strand D, Obrist P et al (2007) The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 26:6979–6988CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Liu Y, Sanchez-Tillo E, Lu X, Huang L, Clem B, Telang S, Jenson AB, Cuatrecasas M, Chesney J, Postigo A et al (2013) Sequential inductions of the ZEB1 transcription factor caused by mutation of Rb and then Ras proteins are required for tumor initiation and progression. J Biol Chem 288:11572–11580CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Liu Y, Sanchez-Tillo E, Lu X, Huang L, Clem B, Telang S, Jenson AB, Cuatrecasas M, Chesney J, Postigo A et al (2014) The ZEB1 transcription factor acts in a negative feedback loop with miR200 downstream of Ras and Rb1 to regulate Bmi1 expression. J Biol Chem 289:4116–4125CrossRefPubMedGoogle Scholar
- 40.Serna E, Lopez-Gines C, Monleon D, Munoz-Hidalgo L, Callaghan RC, Gil-Benso R, Martinetto H, Gregori-Romero A, Gonzalez-Darder J, Cerda-Nicolas M (2014) Correlation between EGFR amplification and the expression of microRNA-200c in primary glioblastoma multiforme. PLoS One 9:e102927CrossRefPubMedPubMedCentralGoogle Scholar
- 41.Joseph JV, Conroy S, Tomar T, Eggens-Meijer E, Bhat K, Copray S, Walenkamp AM, Boddeke E, Balasubramanyian V, Wagemakers M et al (2014) TGF-beta is an inducer of ZEB1-dependent mesenchymal transdifferentiation in glioblastoma that is associated with tumor invasion. Cell Death Dis 5:e1443CrossRefPubMedPubMedCentralGoogle Scholar
- 47.Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE et al (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17:225–234CrossRefPubMedPubMedCentralGoogle Scholar
- 53.Sabourin JC, Ackema KB, Ohayon D, Guichet PO, Perrin FE, Garces A, Ripoll C, Charite J, Simonneau L, Kettenmann H et al (2009) A mesenchymal-like ZEB1(+) niche harbors dorsal radial glial fibrillary acidic protein-positive stem cells in the spinal cord. Stem Cells 27:2722–2733CrossRefPubMedGoogle Scholar