Epigenome Programming by H3.3K27M Mutation Creates a Dependence of Pediatric Glioma on SMARCA4

Yan Mo; Shoufu Duan; Xu Zhang; Xu Hua; Hui Zhou; Hong Jian Wei; Jun Watanabe; Nicholas McQuillan; Zhenyi Su; Wei Gu; Cheng Chia Wu; Christopher R. Vakoc; Rintaro Hashizume; Kenneth Chang; Zhiguo Zhang

doi:10.1158/2159-8290.CD-21-1492

Epigenome Programming by H3.3K27M Mutation Creates a Dependence of Pediatric Glioma on SMARCA4

Yan Mo, Shoufu Duan, Xu Zhang, Xu Hua, Hui Zhou, Hong Jian Wei, Jun Watanabe, Nicholas McQuillan, Zhenyi Su, Wei Gu, Cheng Chia Wu, Christopher R. Vakoc, Rintaro Hashizume, Kenneth Chang, Zhiguo Zhang^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Patients with diffuse midline gliomas that are H3K27 altered (DMG) display a dis-mal 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 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.

Original language	English (US)
Pages (from-to)	2906-2929
Number of pages	24
Journal	Cancer discovery
Volume	12
Issue number	12
DOIs	https://doi.org/10.1158/2159-8290.CD-21-1492
State	Published - Dec 1 2022

Funding

We thank Dr. Oren Becher for the H3.3K27M mouse DMG line and Dr. Jun Qin for the SMARCA4 plasmid. This work is supported by NCI R01 CA204297 (to Z. Zhang), by the Gary and Yael Fegel Family Foundation, the Matheson Foundation (UR010590), St. Baldrick’s Foundation, and the Star and Storm Foundation (to C.-C. Wu). The genome sequencing facility at Columbia University is supported by the Herbert Irving Cancer Center Support Grant (P30CA013696). C.R. Vakoc reports grants and personal fees from Treeline Biosciences and Syro Pharmaceuticals, personal fees from Flare Therapeutics, Roivant Sciences, C4 Therapeutics, and KSQ Therapeutics, and grants from Boehringer Ingelheim outside the submitted work. No disclosures were reported by the other authors.

ASJC Scopus subject areas

Oncology

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@article{e0e20faf6af2476ba20f09218d5503ca,

title = "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 dis-mal 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 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.",

author = "Yan Mo and Shoufu Duan and Xu Zhang and Xu Hua and Hui Zhou and Wei, {Hong Jian} and Jun Watanabe and Nicholas McQuillan and Zhenyi Su and Wei Gu and Wu, {Cheng Chia} and Vakoc, {Christopher R.} and Rintaro Hashizume and Kenneth Chang and Zhiguo Zhang",

note = "Funding Information: We thank Dr. Oren Becher for the H3.3K27M mouse DMG line and Dr. Jun Qin for the SMARCA4 plasmid. This work is supported by NCI R01 CA204297 (to Z. Zhang), by the Gary and Yael Fegel Family Foundation, the Matheson Foundation (UR010590), St. Baldrick{\textquoteright}s Foundation, and the Star and Storm Foundation (to C.-C. Wu). The genome sequencing facility at Columbia University is supported by the Herbert Irving Cancer Center Support Grant (P30CA013696). Funding Information: C.R. Vakoc reports grants and personal fees from Treeline Biosciences and Syro Pharmaceuticals, personal fees from Flare Therapeutics, Roivant Sciences, C4 Therapeutics, and KSQ Therapeutics, and grants from Boehringer Ingelheim outside the submitted work. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2022 American Association for Cancer Research.",

year = "2022",

month = dec,

day = "1",

doi = "10.1158/2159-8290.CD-21-1492",

language = "English (US)",

volume = "12",

pages = "2906--2929",

journal = "Cancer discovery",

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T1 - Epigenome Programming by H3.3K27M Mutation Creates a Dependence of Pediatric Glioma on SMARCA4

AU - Mo, Yan

AU - Duan, Shoufu

AU - Zhang, Xu

AU - Hua, Xu

AU - Zhou, Hui

AU - Wei, Hong Jian

AU - Watanabe, Jun

AU - McQuillan, Nicholas

AU - Su, Zhenyi

AU - Gu, Wei

AU - Wu, Cheng Chia

AU - Vakoc, Christopher R.

AU - Hashizume, Rintaro

AU - Chang, Kenneth

AU - Zhang, Zhiguo

N1 - Funding Information: We thank Dr. Oren Becher for the H3.3K27M mouse DMG line and Dr. Jun Qin for the SMARCA4 plasmid. This work is supported by NCI R01 CA204297 (to Z. Zhang), by the Gary and Yael Fegel Family Foundation, the Matheson Foundation (UR010590), St. Baldrick’s Foundation, and the Star and Storm Foundation (to C.-C. Wu). The genome sequencing facility at Columbia University is supported by the Herbert Irving Cancer Center Support Grant (P30CA013696). Funding Information: C.R. Vakoc reports grants and personal fees from Treeline Biosciences and Syro Pharmaceuticals, personal fees from Flare Therapeutics, Roivant Sciences, C4 Therapeutics, and KSQ Therapeutics, and grants from Boehringer Ingelheim outside the submitted work. No disclosures were reported by the other authors. Publisher Copyright: © 2022 American Association for Cancer Research.

PY - 2022/12/1

Y1 - 2022/12/1

N2 - Patients with diffuse midline gliomas that are H3K27 altered (DMG) display a dis-mal 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 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.

AB - Patients with diffuse midline gliomas that are H3K27 altered (DMG) display a dis-mal 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 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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Epigenome Programming by H3.3K27M Mutation Creates a Dependence of Pediatric Glioma on SMARCA4

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