title: ZEB1 regulates glioma stemness through LIF repression.
abstract: The identification of a stem cell regulatory gene which is aberrantly expressed in glioma and associated with patient survival would increase the understanding of the role of glioma cancer stem cells (GCSCs) in the virulence of gliomas. Interrogating the genomes of over 4000 brain cancers we identified ZEB1 deletion in ~15% (grade II and III) and 50% of glioblastomas. Meta-analysis of ZEB1 copy number status in 2,988 cases of glioma revealed disruptive ZEB1 deletions associated with decreased survival. We identified ZEB1 binding sites within the LIF (stemness factor) promoter region, and demonstrate LIF repression by ZEB1. ZEB1 knockdown in GCSCs caused LIF induction commensurate with GCSC self-renewal and inhibition of differentiation. IFN-γ treatment to GCSCs induced ZEB1 expression, attenuating LIF activities. These findings implicate ZEB1 as a stem cell regulator in glioma which when deleted leads to increased stemness, tumorigenicity and shortened patient survival.
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Lincoln A
authors.initials: LA
authors.lastname: Edwards
authors.affiliation: Neuro-Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Aiguo
authors.initials: A
authors.lastname: Li
authors.affiliation: Biostatistics Core, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Dror
authors.initials: D
authors.lastname: Berel
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Mecca
authors.initials: M
authors.lastname: Madany
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Nam-Ho
authors.initials: NH
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Minzhi
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Mitch
authors.initials: M
authors.lastname: Hymowitz
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Uy
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Jung
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Minlin
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Altan
authors.initials: A
authors.lastname: Rentsendorj
authors.affiliation: Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Xuemo
authors.initials: X
authors.lastname: Fan
authors.affiliation: Neuro-Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA. john.yu@cshs.org.
authors.forename: John S
authors.initials: JS
authors.lastname: Yu
mesh_terms: D017353:Gene Deletion; D018628:Gene Dosage; D005786:Gene Expression Regulation; D005910:Glioma / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000096:biosynthesis*; D060787:Neoplasm Grading; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D012097:Repressor Proteins; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1