ArticleProceedings of the National Academy of Sciences of the United States of America2023
Targeting SWI/SNF ATPases in H3.3K27M diffuse intrinsic pontine gliomas.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 23 citations in OpenAlex.
- Unraveling the secrets of novel PROTACs to improve degradation efficacy.Molecular diversity · 2026Review
- Oncohistone inhibition reshapes tumor-microenvironment communication in Diffuse Midline Glioma (DMG).bioRxiv : the preprint server for biology · 2026Article
- The roles of chromatin remodeling and 3D genome organization in cancers: from mechanistic insights to emerging treatment options.Molecular cancer · 2026Review
- Diffuse Midline Gliomas: Clinical, Diagnostic, and Therapeutic Perspectives.Biomedicines · 2026Review
- Epigenetic mechanisms and therapeutic advances in diffuse midline glioma (Review).Oncology reports · 2026Review
- SMARCA4 regulates SMARCAD1 expression for toleration of replication stress in non-small cell lung cancer.Fujita medical journal · 2026Article
- Decoding Gene Expression Changes in Cerebral Tumors: Before and After Radiotherapy.Medicinal research reviews · 2025Review
- Review
- Review
- Targeting ALDH16A1 mediated thioredoxin lysosomal degradation to enhance ferroptosis susceptibility in SMARCA4-deficient NSCLC.Nature communications · 2025Article
- Death-ision: the link between cellular resilience and cancer resistance to treatments.Molecular cancer · 2025Review
- Chromatin remodeling and cancer: the critical influence of the SWI/SNF complex.Epigenetics & chromatin · 2025Review
- An oncohistone-driven H3.3K27M/CREB5/ID1 axis maintains the stemness and malignancy of diffuse intrinsic pontine glioma.Nature communications · 2025Article
- Predicting hepatocellular carcinoma outcomes and immune therapy response with ATP-dependent chromatin remodeling-related genes, highlighting MORF4L1 as a promising target.Cancer cell international · 2025Article
- Tight junction proteins in glial tumors development and progression.Frontiers in cellular neuroscience · 2025Review
- Epigenetic reprogramming in pediatric gliomas: from molecular mechanisms to therapeutic implications.Trends in cancer · 2024Review
- Developmental origins shape the paediatric cancer genome.Nature reviews. Cancer · 2024Review
- Targeting SMAD-Dependent Signaling: Considerations in Epithelial and Mesenchymal Solid Tumors.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications.Epigenomes · 2024Review
- Emerging roles of cancer-associated histone mutations in genomic instabilities.Frontiers in cell and developmental biology · 2024Review
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 3 countries.
Funding
Abstract
Diffuse midline gliomas (DMGs) including diffuse intrinsic pontine gliomas (DIPGs) bearing lysine-to-methionine mutations in histone H3 at lysine 27 (H3K27M) are lethal childhood brain cancers. These tumors harbor a global reduction in the transcriptional repressive mark H3K27me3 accompanied by an increase in the transcriptional activation mark H3K27ac. We postulated that H3K27M mutations, in addition to altering H3K27 modifications, reprogram the master chromatin remodeling switch/sucrose nonfermentable (SWI/SNF) complex. The SWI/SNF complex can exist in two main forms termed BAF and PBAF that play central roles in neurodevelopment and cancer. Moreover, BAF antagonizes PRC2, the main enzyme catalyzing H3K27me3. We demonstrate that H3K27M gliomas show increased protein levels of the SWI/SNF complex ATPase subunits SMARCA4 and SMARCA2, and the PBAF component PBRM1. Additionally, knockdown of mutant H3K27M lowered SMARCA4 protein levels. The proteolysis targeting chimera (PROTAC) AU-15330 that simultaneously targets SMARCA4, SMARCA2, and PBRM1 for degradation exhibits cytotoxicity in H3.3K27M but not H3 wild-type cells. AU-15330 lowered chromatin accessibility measured by ATAC-Seq at nonpromoter regions and reduced global H3K27ac levels. Integrated analysis of gene expression, proteomics, and chromatin accessibility in AU-15330-treated cells demonstrated reduction in the levels of FOXO1, a key member of the forkhead family of transcription factors. Moreover, genetic or pharmacologic targeting of FOXO1 resulted in cell death in H3K27M cells. Overall, our results suggest that H3K27M up-regulates SMARCA4 levels and combined targeting of SWI/SNF ATPases in H3.3K27M can serve as a potent therapeutic strategy for these deadly childhood brain tumors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.