WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma
© 2023 Mitchell et al.; Published by Cold Spring Harbor Laboratory Press..
SOX2 motif. Use of a SOX2/OCT4 reporter demonstrated that WDR5 inhibitor treatment diminished cells with high reporter activity. Furthermore, WDR5 inhibitor treatment and WDR5 knockdown altered the stem cell state, disrupting CSC in vitro growth and self-renewal, as well as in vivo tumor growth. These findings highlight the role of WDR5 and the WRAD complex in maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:37 |
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| Enthalten in: |
Genes & development - 37(2023), 3-4 vom: 01. Feb., Seite 86-102 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mitchell, Kelly [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.03.2023 Date Revised 02.08.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1101/gad.349803.122 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM352422475 |
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| 100 | 1 | |a Mitchell, Kelly |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 21.03.2023 | ||
| 500 | |a Date Revised 02.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 Mitchell et al.; Published by Cold Spring Harbor Laboratory Press. | ||
| 520 | |a Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors driven by populations of cancer stem cells (CSCs). However, 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 (H3K4me), associated with positive regulation of transcription. In GBM CSCs, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, including the POU5F1(OCT4)::SOX2 motif. Use of a SOX2/OCT4 reporter demonstrated that WDR5 inhibitor treatment diminished cells with high reporter activity. Furthermore, WDR5 inhibitor treatment and WDR5 knockdown altered the stem cell state, disrupting CSC in vitro growth and self-renewal, as well as in vivo tumor growth. These findings highlight the role of WDR5 and the WRAD complex in maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a epigenetics | |
| 650 | 4 | |a glioblastoma | |
| 650 | 4 | |a stem cell | |
| 650 | 7 | |a Histone-Lysine N-Methyltransferase |2 NLM | |
| 650 | 7 | |a EC 2.1.1.43 |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a WDR5 protein, human |2 NLM | |
| 650 | 7 | |a Intracellular Signaling Peptides and Proteins |2 NLM | |
| 700 | 1 | |a Sprowls, Samuel A |e verfasserin |4 aut | |
| 700 | 1 | |a Arora, Sonali |e verfasserin |4 aut | |
| 700 | 1 | |a Shakya, Sajina |e verfasserin |4 aut | |
| 700 | 1 | |a Silver, Daniel J |e verfasserin |4 aut | |
| 700 | 1 | |a Goins, Christopher M |e verfasserin |4 aut | |
| 700 | 1 | |a Wallace, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Roversi, Gustavo |e verfasserin |4 aut | |
| 700 | 1 | |a Schafer, Rachel E |e verfasserin |4 aut | |
| 700 | 1 | |a Kay, Kristen |e verfasserin |4 aut | |
| 700 | 1 | |a Miller, Tyler E |e verfasserin |4 aut | |
| 700 | 1 | |a Lauko, Adam |e verfasserin |4 aut | |
| 700 | 1 | |a Bassett, John |e verfasserin |4 aut | |
| 700 | 1 | |a Kashyap, Anjali |e verfasserin |4 aut | |
| 700 | 1 | |a D'Amato Kass, Jonathan |e verfasserin |4 aut | |
| 700 | 1 | |a Mulkearns-Hubert, Erin E |e verfasserin |4 aut | |
| 700 | 1 | |a Johnson, Sadie |e verfasserin |4 aut | |
| 700 | 1 | |a Alvarado, Joseph |e verfasserin |4 aut | |
| 700 | 1 | |a Rich, Jeremy N |e verfasserin |4 aut | |
| 700 | 1 | |a Holland, Eric C |e verfasserin |4 aut | |
| 700 | 1 | |a Paddison, Patrick J |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Anoop P |e verfasserin |4 aut | |
| 700 | 1 | |a Stauffer, Shaun R |e verfasserin |4 aut | |
| 700 | 1 | |a Hubert, Christopher G |e verfasserin |4 aut | |
| 700 | 1 | |a Lathia, Justin D |e verfasserin |4 aut | |
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