Sexual dimorphism of ZEB1 expression and function in glioblastoma

Whittaker, Ben E., Davies, Samuel, Kwan, Jeffrey C. F., Gordon-Smith, Annabelle and Siebzehnrubl, Florian A. ORCID: https://orcid.org/0000-0001-8411-8775 2026. Sexual dimorphism of ZEB1 expression and function in glioblastoma. Cells 15 (15) , 1428. 10.3390/cells15151428

PDF - Published Version Available under License Creative Commons Attribution. Download (6MB)

Abstract

Glioblastoma (GBM) exhibits marked sex differences in incidence, outcome, and molecular regulation, yet the mechanisms underlying these disparities remain poorly defined. ZEB1 is a neurodevelopmental transcription factor implicated in GBM progression and cellular plasticity, but its prognostic and functional relevance may differ by sex. Here, we analyzed TCGA-GBM transcriptomic and clinical data to assess the relationship between ZEB1 expression, patient sex, and survival and to identify sex-specific transcriptional programs associated with ZEB1. Patients were stratified by ZEB1 expression and sex, followed by differential expression analysis, functional enrichment, and survival modeling. High ZEB1 expression was associated with improved overall survival in female patients but not in male patients. Sex-stratified transcriptomic analysis revealed distinct ZEB1-associated gene expression signatures, with enrichment of chromatin-modifying and demethylase-related pathways among male–female comparisons. Candidate Y-linked epigenetic regulators, including KDM5D and UTY, were differentially expressed in ZEB1-high male tumors. qPCR validation in male and female patient-derived GBM cell lines supported sex-dependent regulation of these candidates and showed that KDM5D and UTY expression was reduced following ZEB1 knockdown in male cells. Together, these findings identify a sex-dependent prognostic role for ZEB1 in GBM and suggest that ZEB1 interacts with sex-chromosome-linked epigenetic regulators to shape tumor transcriptional states.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Biosciences
Publisher:	MDPI
ISSN:	2073-4409
Date of First Compliant Deposit:	12 August 2026
Date of Acceptance:	27 July 2026
Last Modified:	12 Aug 2026 11:35
URI:	https://orca.cardiff.ac.uk/id/eprint/188943

Actions (repository staff only)

Edit Item