ZEB1 regulates glioma stemness through LIF repression.
Lincoln A Edwards1, Aiguo Li2, Dror Berel3
1Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Scientific Reports
|March 2, 2017
Summary
ZEB1 gene deletion in glioma correlates with decreased patient survival and increased cancer stem cell self-renewal. Restoring ZEB1 may offer therapeutic potential for aggressive brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioma cancer stem cells (GCSCs) drive tumor virulence and poor patient survival.
- Understanding stem cell regulatory genes in glioma is crucial for therapeutic development.
Purpose of the Study:
- To identify stem cell regulatory genes in glioma associated with patient survival.
- To investigate the role of ZEB1 in regulating GCSC properties and its clinical significance.
Main Methods:
- Genome-wide interrogation of over 4000 brain cancers to identify ZEB1 deletions.
- Meta-analysis of ZEB1 copy number status in 2,988 glioma cases.
- Experimental validation of ZEB1 binding sites in the LIF promoter and its effect on GCSC self-renewal and differentiation.
Main Results:
- ZEB1 deletion was identified in 15% of low-grade gliomas and 50% of glioblastomas.
- Disruptive ZEB1 deletions were significantly associated with decreased patient survival.
- ZEB1 represses LIF (a stemness factor); ZEB1 knockdown induced LIF, promoting GCSC self-renewal and inhibiting differentiation.
- IFN-γ treatment increased ZEB1 expression, reducing LIF activity in GCSCs.
Conclusions:
- ZEB1 acts as a crucial stem cell regulator in glioma.
- ZEB1 deletion promotes GCSC stemness and tumorigenicity, leading to poorer patient outcomes.
- Targeting ZEB1 or its pathway may represent a novel therapeutic strategy for glioma.
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