Summary
Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We employed spatially resolved loss-of-function screening in GBM patient-derived organoids to identify essential epigenetic regulators and identified WDR5 as indispensable for CSCs. WDR5 is a component of the WRAD complex, which promotes SET1-family-mediated Lys4 methylation of histone H3, associated with positive regulation of transcription. Genetic and pharmacologic inhibition of WDR5 reduced growth and self-renewal of CSCs as well as CSC-mediated tumor growth. Further, WDR5 inhibitors partially blocked WRAD complex assembly, reduced H3K4 trimethylation, and inhibited tumor growth. These findings highlight the role of WDR5 and the WRAD complex in CSCs for maintaining the CSC state and provide a rationale for therapeutic development of WRAD complex inhibitors for GBM and other advanced cancers.
Competing Interest Statement
The authors have declared no competing interest.
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