title: ZEB1 expression is increased in IDH1-mutant lower-grade gliomas.
abstract: 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.
authors: Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, 9000 Rockville Pike, Building 10 Room 3D17, Bethesda, MD, 20892, USA. Cody.Nesvick@gmail.com.|Department of Neurologic Surgery, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA. Cody.Nesvick@gmail.com.
authors: Cody L
authors: CL
authors: Nesvick
authors: Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, 9000 Rockville Pike, Building 10 Room 3D17, Bethesda, MD, 20892, USA.
authors: Chao
authors: C
authors: Zhang
authors: Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, 9000 Rockville Pike, Building 10 Room 3D17, Bethesda, MD, 20892, USA.
authors: Nancy A
authors: NA
authors: Edwards
authors: Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, 9000 Rockville Pike, Building 10 Room 3D17, Bethesda, MD, 20892, USA.|Department of Orthopaedic Surgery, Stanford University, 450 Broadway Street, Pavilion C, 4th Floor, Redwood City, CA, 94063, USA.
authors: Blake K
authors: BK
authors: Montgomery
authors: Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, 9000 Rockville Pike, Building 10 Room 3D17, Bethesda, MD, 20892, USA.|Department of Neurological Surgery, The George Washington University, 2150 Pennsylvania Avenue NW, Suite 7-420, Washington, DC, 20037, USA.
authors: Michaela
authors: M
authors: Lee
authors: Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, 9000 Rockville Pike, Building 10 Room 3D17, Bethesda, MD, 20892, USA.|Neuro-Oncology Branch, National Cancer Institute, Building 37, Room 1142E, Bethesda, MD, 20892, USA.
authors: Chunzhang
authors: C
authors: Yang
authors: Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, 9000 Rockville Pike, Building 10 Room 3D17, Bethesda, MD, 20892, USA.
authors: Herui
authors: H
authors: Wang
authors: Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, 9000 Rockville Pike, Building 10 Room 3D17, Bethesda, MD, 20892, USA.
authors: Dongwang
authors: D
authors: Zhu
authors: Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, 9000 Rockville Pike, Building 10 Room 3D17, Bethesda, MD, 20892, USA.
authors: John D
authors: JD
authors: Heiss
authors: Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, 9000 Rockville Pike, Building 10 Room 3D17, Bethesda, MD, 20892, USA.
authors: Marsha J
authors: MJ
authors: Merrill
authors: Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, 9000 Rockville Pike, Building 10 Room 3D17, Bethesda, MD, 20892, USA.
authors: Abhik
authors: A
authors: Ray-Chaudhury
authors: Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, 9000 Rockville Pike, Building 10 Room 3D17, Bethesda, MD, 20892, USA. ZhuangP@ninds.nih.gov.
authors: Zhengping
authors: Z
authors: Zhuang
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D016208:Databases, Factual / Q000706:statistics & numerical data; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D009154:Mutation / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D013223:Statistics as Topic; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: Epithelial-mesenchymal transition; IDH; Lower-grade glioma; ZEB1