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GEO help: Mouse over screen elements for information. |
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Status |
Public on Jan 26, 2023 |
Title |
WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma |
Organism |
Homo sapiens |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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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 developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche and identified WDR5 as indispensable for this population. 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 blocked WRAD complex assembly, reduced H3K4 trimethylation, and inhibited tumor growth. These findings highlight the role of WDR5 and the WRAD complex for maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.
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Overall design |
CUT&Tag data from 4 replicates each for DMSO and WDR5 WIN site inhibitor (C16)
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Contributor(s) |
Mitchell K, Shakya S, Arora S, Silver DJ, Goins CM, Wallace L, Roversi G, Schafer R, Kay K, Miller TE, Lauko A, Bassett J, D'Amato Kass J, Kashyap A, Mulkearns-Hubert EE, Johnson S, Alvarado J, Rich JN, Paddison PJ, Patel AP, Stauffer SR, Hubert CG, Lathia JD |
Citation missing |
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Submission date |
Mar 21, 2022 |
Last update date |
Jan 29, 2023 |
Contact name |
Sonali Arora |
E-mail(s) |
sarora@fredhutch.org
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Organization name |
FHCRC
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Street address |
1100 Fairview Ave N,
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City |
Seattle |
State/province |
WA |
ZIP/Postal code |
98109 |
Country |
USA |
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Platforms (1) |
GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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Samples (8)
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Relations |
BioProject |
PRJNA818419 |
Supplementary file |
Size |
Download |
File type/resource |
GSE199110_RAW.tar |
4.4 Mb |
(http)(custom) |
TAR (of NARROWPEAK) |
SRA Run Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |
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