期刊
CANCER DISCOVERY
卷 12, 期 12, 页码 2906-2929出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-21-1492
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资金
- NCI [R01 CA204297]
- Matheson Foundation [UR010590]
- St. Baldricks Foundation
- Star and Storm Foundation
- Herbert Irving Cancer Center Support Grant [P30CA013696]
- Gary and Yael Fegel Family Foundation
The catalytic subunit of the SWI/SNF chromatin remodeling complex, SMARCA4, is essential for the proliferation and growth of diffuse midline gliomas with H3K27M mutation. This discovery provides a potential therapeutic approach to this deadly pediatric glioma.
Patients with diffuse midline gliomas that are H3K27 altered (DMG) display a dis-mal prognosis. However, the molecular mechanisms underlying DMG tumorigenesis remain poorly defi ned. 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 extra -cellular 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 discov-ered 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.
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