Epigenome Programming by H3.3K27M Mutation Creates a Dependence of Pediatric Glioma on SMARCA4
- PMID: 36305747
- PMCID: PMC9722525
- DOI: 10.1158/2159-8290.CD-21-1492
Epigenome Programming by H3.3K27M Mutation Creates a Dependence of Pediatric Glioma on SMARCA4
Abstract
Patients with diffuse midline gliomas that are H3K27 altered (DMG) display a dismal prognosis. However, the molecular mechanisms underlying DMG tumorigenesis remain poorly defined. Here we show that SMARCA4, the catalytic subunit of the mammalian SWI/SNF chromatin remodeling complex, is essential for the proliferation, migration, and invasion of DMG cells and tumor growth in patient-derived DMG xenograft models. SMARCA4 colocalizes with SOX10 at gene regulatory elements to control the expression of genes involved in cell growth and the extracellular matrix (ECM). Moreover, SMARCA4 chromatin binding is reduced upon depletion of SOX10 or H3.3K27M, a mutation occurring in about 60% DMG tumors. Furthermore, the SMARCA4 occupancy at enhancers marked by both SOX10 and H3K27 acetylation is reduced the most upon depleting the H3.3K27M mutation. Taken together, our results support a model in which epigenome reprogramming by H3.3K27M creates a dependence on SMARCA4-mediated chromatin remodeling to drive gene expression and the pathogenesis of H3.3K27M DMG.
Significance: DMG is a deadly pediatric glioma currently without effective treatments. We discovered that the chromatin remodeler SMARCA4 is essential for the proliferation of DMG with H3K27M mutation in vitro and in vivo, identifying a potentially novel therapeutic approach to this disease. See related commentary by Beytagh and Weiss, p. 2730. See related article by Panditharatna et al., p. 2880. This article is highlighted in the In This Issue feature, p. 2711.
©2022 American Association for Cancer Research.
Conflict of interest statement
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Comment in
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BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma.Cancer Discov. 2022 Dec 2;12(12):2880-2905. doi: 10.1158/2159-8290.CD-21-1491. Cancer Discov. 2022. PMID: 36305736 Free PMC article.
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Epigenetic Rewiring Underlies SMARCA4-Dependent Maintenance of Progenitor State in Pediatric H3K27M Diffuse Midline Glioma.Cancer Discov. 2022 Dec 2;12(12):2730-2732. doi: 10.1158/2159-8290.CD-22-1030. Cancer Discov. 2022. PMID: 36458436 Free PMC article.
Comment on
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BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma.Cancer Discov. 2022 Dec 2;12(12):2880-2905. doi: 10.1158/2159-8290.CD-21-1491. Cancer Discov. 2022. PMID: 36305736 Free PMC article.
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