ArticleCancer research2022
Loss of H3K27 Trimethylation Promotes Radiotherapy Resistance in Medulloblastoma and Induces an Actionable Vulnerability to BET Inhibition.
Article in Cancer research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 40 citations in OpenAlex.
- Review
- Nanomaterials reshaping cancer radiotherapy: Radiosensitization mechanisms, delivery and theranostic platforms, multimodal synergy, and clinical translation strategies.Materials today. Bio · 2026Review
- Advancing Medulloblastoma Treatment: Molecular Mechanisms, Drug Repurposing, and Precision Therapies.Molecular diagnosis & therapy · 2026Review
- Amphiregulin and Epiregulin Confer Radioresistance in Esophageal Squamous Cell Carcinoma Through Oxidative Phosphorylation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Epigenomic and Metabolic Interplay in the Development of Metastatic Brain Tumors.Oncology research · 2026Review
- Advancing cancer radiotherapy: Harnessing radiosensitizers and nanotechnology for enhanced tumor control.International journal of pharmaceutics: X · 2025Review
- How histone modifications influence cellular radiosensitivity: Pharmaceutically targeting epigenetic regulators as a promising avenue to overcome radioresistance.Acta pharmaceutica Sinica. B · 2025Review
- Ezh2 Loss-of-Function Alters Zebrafish Cerebellum Development.International journal of molecular sciences · 2025Article
- Review
- Prognostic value of immunohistochemical staining for H3K27me3 and EZH2 in astrocytoma, IDH-mutant.Journal of neuro-oncology · 2025Article
- Ferroptosis Transcriptional Regulation and Prognostic Impact in Medulloblastoma Subtypes Revealed by RNA-Seq.Antioxidants (Basel, Switzerland) · 2025Article
- Ephrin-Eph signaling: an important regulator of epithelial integrity and barrier function.Tissue barriers · 2025Review
- NSUN6-mediated 5-methylcytosine modification of NDRG1 mRNA promotes radioresistance in cervical cancer.Molecular cancer · 2024Article
- Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies.Cancers · 2024Review
- miR-124-3p and miR-194-5p regulation of the PI3K/AKT pathway via ROR2 in medulloblastoma progression.Cancer gene therapy · 2024Article
- Eph receptors and ephrins in cancer progression.Nature reviews. Cancer · 2024Review
- Exploring the Molecular Complexity of Medulloblastoma: Implications for Diagnosis and Treatment.Diagnostics (Basel, Switzerland) · 2023Review
- Targeting H3K27me3 loss in pediatric brain tumors - a perspective on epigenetically guided cancer therapy.Oncotarget · 2023Article
- Molecular characterisation defines clinically-actionable heterogeneity within Group 4 medulloblastoma and improves disease risk-stratification.Acta neuropathologica · 2023Article
- Exploiting radiation immunostimulatory effects to improve glioblastoma outcome.Neuro-oncology · 2023Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Medulloblastoma has been categorized into four subgroups based on genetic, epigenetic, and transcriptional profiling. Radiation is used for treating medulloblastoma regardless of the subgroup. A better understanding of the molecular pathways determining radiotherapy response could help improve medulloblastoma treatment. Here, we investigated the role of the EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit)-dependent histone H3K27 trimethylation in radiotherapy response in medulloblastoma. The tumors in 47.2% of patients with group 3 and 4 medulloblastoma displayed H3K27me3 deficiency. Loss of H3K27me3 was associated with a radioresistant phenotype, high relapse rates, and poor overall survival. In H3K27me3-deficient medulloblastoma cells, an epigenetic switch from H3K27me3 to H3K27ac occurred at specific genomic loci, altering the transcriptional profile. The resulting upregulation of EPHA2 stimulated excessive activation of the prosurvival AKT signaling pathway, leading to radiotherapy resistance. Bromodomain and extraterminal motif (BET) inhibition overcame radiation resistance in H3K27me3-deficient medulloblastoma cells by suppressing H3K27ac levels, blunting EPHA2 overexpression, and mitigating excessive AKT signaling. In addition, BET inhibition sensitized medulloblastoma cells to radiation by enhancing the apoptotic response through suppression of Bcl-xL and upregulation of Bim. This work demonstrates a novel mechanism of radiation resistance in medulloblastoma and identifies an epigenetic marker predictive of radiotherapy response. On the basis of these findings, we propose an epigenetically guided treatment approach targeting radiotherapy resistance in patients with medulloblastoma. SIGNIFICANCE: This study demonstrates a novel epigenetic mechanism of radiation resistance in medulloblastoma and identifies a therapeutic approach to improve outcomes in these patients.
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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.