WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma.

Autor:	Mitchell K; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA.; Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA., Sprowls SA; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA.; Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA., Arora S; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington 98109, USA., Shakya S; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA., Silver DJ; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA.; Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA.; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44106, USA., Goins CM; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA; lathiaj@ccf.org christopher.hubert@case.edu., Wallace L; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA., Roversi G; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA.; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44106, USA., Schafer RE; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA.; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44106, USA., Kay K; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA., Miller TE; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA., Lauko A; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA.; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44106, USA.; Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.; Medical Scientist Training Program, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA., Bassett J; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington 98109, USA., Kashyap A; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA., D'Amato Kass J; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA., Mulkearns-Hubert EE; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA.; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44106, USA., Johnson S; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA., Alvarado J; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA., Rich JN; University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA., Holland EC; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington 98109, USA., Paddison PJ; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington 98109, USA., Patel AP; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington 98109, USA.; Department of Neurological Surgery, University of Washington, Seattle, Washington 98195, USA., Stauffer SR; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA., Hubert CG; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA.; Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA.; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44106, USA., Lathia JD; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA; lathiaj@ccf.org christopher.hubert@case.edu.; Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA.; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44106, USA.; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio 44106, USA.
Jazyk:	angličtina
Zdroj:	Genes & development [Genes Dev] 2023 Feb 01; Vol. 37 (3-4), pp. 86-102. Date of Electronic Publication: 2023 Feb 02.
DOI:	10.1101/gad.349803.122
Abstrakt:	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. (© 2023 Mitchell et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
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