ZEB1 regulates glioma stemness through LIF repression

Lincoln A Edwards,Rachel Jung,Minlin Xu,Altan Rentsendorj,John S Yu,Aiguo Li,Benjamin Uy,Nam-Ho Kim,Dror Berel,Wei Zhang,Keith L Black,Minzhi Liu,Xuemo Fan,Mecca Madany,Mitch Hymowitz

doi:10.1038/s41598-017-00106-x

Lincoln A Edwards, Rachel Jung + Show 13 more

Open Access

https://doi.org/10.1038/s41598-017-00106-x

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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.

Highlights

The genetic underpinnings of how glioma cancer stem cells (GCSCs) propagate tumors and how this affects patient survival is not well understood
We studied the role of Zinc Finger E-Box Binding Homeobox 1 gene (ZEB1) loss in maintaining glioma cancer stem cell properties and its impact on patient survival in gliomas
Our data indicated that ZEB1 expression is lost in a significant number of glioma patients, and that the cause of ZEB1 loss is due in large part to heterozygous deletions in both GBMs and lower grade gliomas with frequent loss of heterozygosity (LOH) in at least 20% of glioma patients

Summary

Introduction

The genetic underpinnings of how glioma cancer stem cells (GCSCs) propagate tumors and how this affects patient survival is not well understood. Identifying genes that control stem cell regulation, especially those in which mutations or a loss in copy number of these stem cell regulatory genes can support the propagation of the cancer, is fundamental to the basic understanding of brain cancer lethality. We have identified ZEB1 as a stem cell regulator in brain cancer which when deleted leads to increased stemness, tumorigenicity and shortened patient survival. These mutations along with other recently observed mutations of ZEB1 in gliomas could account for the decreased ZEB1 expression[13, 14] These findings uncover important information about stem cell regulation by ZEB1 expression, copy number level in both GBMs and low grade gliomas with implications for prognostication and treatment of gliomas. (d) Estimated Kaplan-Meier survival curves for 451 low grade glioma patients (left) for deleted (DEL) and wildtype (WT) copy number.

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