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

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

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

Cited by 22 publications

(10 citation statements)

References 85 publications

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“…The anti-cancer effects of AU-15330 were attributed to the loss of SMARCA4. SMARCA4 was found to maintain gliomas in an undifferentiated stem cell state, regulate genes involved in cell growth and extracellular matrix, and promote tumor growth in vivo in an H3K27M-dependent manner [136,137]. These studies demonstrate that AU-15330 suppresses SWI/SNF activity to exert anti-cancer effects on multiple cancer types driven by oncogenic enhancer circuitry.…”

Section: Targeting Swi/snf Family VIII Bromodomainsmentioning

confidence: 80%

“…BRM014 and other ATPase inhibitors elicit very rapid changes in chromatin accessibility, occurring within minutes [59,60]. BRM014 potently inhibited the growth of an aggressive type of glioma harboring the histone H3 lysine 27 to a methionine mutation (H3K27M) in vitro and in vivo [136,137]. An ATPase degrader, JQ-dS-4, constructed by linking a BRG1 ATPase inhibitor to a phthalimide, which is a target for cereblon (CRBN) ubiquitin ligase, led to a reduction in chromatin accessibility at BRG1 binding sites and reduced the proliferation of H3K27M-driven gliomas.…”

Section: Inhibitors Of Swi/snf Catalytic Activitymentioning

confidence: 99%

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Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Dreier,

Walia,

de la Serna

2024

Epigenomes

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SWI/SNF enzymes are heterogeneous multi-subunit complexes that utilize the energy from ATP hydrolysis to remodel chromatin structure, facilitating transcription, DNA replication, and repair. In mammalian cells, distinct sub-complexes, including cBAF, ncBAF, and PBAF exhibit varying subunit compositions and have different genomic functions. Alterations in the SWI/SNF complex and sub-complex functions are a prominent feature in cancer, making them attractive targets for therapeutic intervention. Current strategies in cancer therapeutics involve the use of pharmacological agents designed to bind and disrupt the activity of SWI/SNF complexes or specific sub-complexes. Inhibitors targeting the catalytic subunits, SMARCA4/2, and small molecules binding SWI/SNF bromodomains are the primary approaches for suppressing SWI/SNF function. Proteolysis-targeting chimeras (PROTACs) were generated by the covalent linkage of the bromodomain or ATPase-binding ligand to an E3 ligase-binding moiety. This engineered connection promotes the degradation of specific SWI/SNF subunits, enhancing and extending the impact of this pharmacological intervention in some cases. Extensive preclinical studies have underscored the therapeutic potential of these drugs across diverse cancer types. Encouragingly, some of these agents have progressed from preclinical research to clinical trials, indicating a promising stride toward the development of effective cancer therapeutics targeting SWI/SNF complex and sub-complex functions.

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Section: Targeting Swi/snf Family VIII Bromodomainsmentioning

confidence: 80%

Section: Inhibitors Of Swi/snf Catalytic Activitymentioning

confidence: 99%

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Dreier,

Walia,

de la Serna

2024

Epigenomes

View full text Add to dashboard Cite

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“…SOX10 is a transcription factor implicated in oligodendroglial differentiation and is overexpressed and hypomethylated in histone-mutant glioma, with a key functional role in viability, migration, and invasion of DIPG cells. 34 , 35 Another gene of interest that was identified among the top genes by promoter JSD was CXCR4. CXCR4 has striking hypermethylation, increased JSD, and increased methylation entropy directly over the promoter region ( Figure 4b ).…”

Section: Resultsmentioning

confidence: 99%

DNA methylation landscapes in DIPG reveal methylome variability that can be modified pharmacologically

Tetens,

Martin,

Arnold

et al. 2024

Neuro-Oncology Advances

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Diffuse intrinsic pontine glioma (DIPG) is a uniformly lethal brainstem tumor of childhood, driven by histone H3 K27M mutation and resultant epigenetic dysregulation. Epigenomic analyses of DIPG have shown global loss of repressive chromatin marks accompanied by DNA hypomethylation. However, studies providing a static view of the epigenome do not adequately capture the regulatory underpinnings of DIPG cellular heterogeneity and plasticity. To address this, we performed whole-genome bisulfite sequencing (WGBS) on a large panel of primary DIPG specimens and applied a novel framework for analysis of DNA methylation variability, permitting the derivation of comprehensive genome-wide DNA methylation potential energy landscapes that capture intrinsic epigenetic variation. We show that DIPG has a markedly disordered epigenome with increasingly stochastic DNA methylation at genes regulating pluripotency and developmental identity, potentially enabling cells to sample diverse transcriptional programs and differentiation states. The DIPG epigenetic landscape was responsive to treatment with the hypomethylating agent decitabine, which produced genome-wide demethylation and reduced the stochasticity of DNA methylation at active enhancers and bivalent promoters. Decitabine treatment elicited changes in gene expression, including upregulation of immune signaling such as the interferon response, STING, and MHC class I expression, and sensitized cells to the effects of histone deacetylase inhibition. This study provides a resource for understanding the epigenetic instability that underlies DIPG heterogeneity. It suggests the application of epigenetic therapies to constrain the range of epigenetic states available to DIPG cells, as well as the use of decitabine in priming for immune-based therapies.

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“…S2D; Additional file 11 : Table S6). Among them, SMARCA4, the top hit in the list for rGBM cells, is involved in cell growth and ECM organization, and is essential for proliferation and migration in diffuse midline glioma [ 47 ]. Knockdown of the SMARCA4 gene in MCF-10A cells has been shown to result in downregulation of ECM genes [ 48 ].…”

Section: Resultsmentioning

confidence: 99%

Decoding key cell sub-populations and molecular alterations in glioblastoma at recurrence by single-cell analysis

Wang,

Sun,

Wang

et al. 2023

acta neuropathol commun

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Glioblastoma (GBM) is the most frequent malignant brain tumor, the relapse of which is unavoidable following standard treatment. However, the effective treatment for recurrent GBM is lacking, necessitating the understanding of key mechanisms driving tumor recurrence and the identification of new targets for intervention. Here, we integrated single-cell RNA-sequencing data spanning 36 patient-matched primary and recurrent GBM (pGBM and rGBM) specimens, with 6 longitudinal GBM spatial transcriptomics to explore molecular alterations at recurrence, with each cell type characterized in parallel. Genes involved in extracellular matrix (ECM) organization are preferentially enriched in rGBM cells, and MAFK is highlighted as a potential regulator. Notably, we uncover a unique subpopulation of GBM cells that is much less detected in pGBM and highly expresses ECM and mesenchyme related genes, suggesting it may contribute to the molecular transition of rGBM. Further regulatory network analysis reveals that transcription factors, such as NFATC4 and activator protein 1 members, may function as hub regulators. All non-tumor cells alter their specific sets of genes as well and certain subgroups of myeloid cells appear to be physically associated with the mesenchyme-like GBM subpopulation. Altogether, our study provides new insights into the molecular understanding of GBM relapse and candidate targets for rGBM treatment.

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

Cited by 22 publications

References 85 publications

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

DNA methylation landscapes in DIPG reveal methylome variability that can be modified pharmacologically

Decoding key cell sub-populations and molecular alterations in glioblastoma at recurrence by single-cell analysis

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