ZEB1 regulates glioma stemness through LIF repression

• Published in: Scientific reports Vol. 7; no. 1; p. 69
• Main Authors: Edwards, Lincoln A., Li, Aiguo, Berel, Dror, Madany, Mecca, Kim, Nam-Ho, Liu, Minzhi, Hymowitz, Mitch, Uy, Benjamin, Jung, Rachel, Xu, Minlin, Black, Keith L., Rentsendorj, Altan, Fan, Xuemo, Zhang, Wei, Yu, John S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28-02-2017; Nature Portfolio
• Subjects: 13/100; 13/106; 13/109; 13/31; 13/44; 14/1; 14/19; 38/22; 38/23; 38/77; 631/67/71; 692/4028/67/1922; Humanities and Social Sciences; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-00106-x

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.