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Review Open Access

Epigenetic mechanisms and therapeutic advances in diffuse midline glioma (Review)

  • Authors:
    • Wenbo Wu
    • Wenlin Chen
    • Wenbin Ma
    • Yu Wang
  • View Affiliations / Copyright

    Affiliations: Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital (East), Beijing 100730, P.R. China
    Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 50
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    Published online on: January 20, 2026
       https://doi.org/10.3892/or.2026.9055
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Abstract

Gliomas are the most common primary malignant tumors of the central nervous system in adults, with diffuse midline gliomas (DMG) being particularly aggressive and associated with inferior survival rate. Notwithstanding advances in molecular diagnostics and epigenetics, the specific pathological mechanisms of DMG remain to be fully elucidated. A series of studies have demonstrated that histone modifications, particularly the histone H3 lysine 27 (H3K27)M mutation, play a pivotal role in the development and progression of DMG. The mutation disrupts histone methylation and acetylation to induce widespread gene expression abnormalities, tumor aggressiveness and treatment resistance. Conventional treatments such as surgery, local radiotherapy and chemotherapy offer limited efficacy. However, emerging precision therapies targeting histone mutations, epigenetic modifications and innovative immunotherapies show promise in improving outcomes. The present study provided a comprehensive overview of the molecular mechanisms, epigenetic characteristics and the latest therapeutic advances in DMG. By investigating the H3K27M mutation and its associated epigenetic mechanisms, the present review aimed to establish theoretical frameworks and research avenues for developing precise therapeutic strategies for DMG, thus contributing to advancing the field of personalized medicine.

View Figures

Figure 1

H3K27M mutation in diffuse midline
glioma. The H3K27M mutation markedly reduces H3K27me3 levels by
inhibiting the EZH2 methyltransferase activity of the PRC2 complex,
leading to disrupted methylation regulation of tumor suppressor
genes and inducing widespread transcriptional abnormalities. This
mutation promotes uncontrolled cell cycle progression, exemplified
by dysregulation of the CDK4/6-p16 pathway and enhances tumor cell
proliferation and invasion through the activation of key signaling
pathways, including MAPK/ERK, PI3K/AKT/mTOR and JAK/STAT. The
H3K27M mutation also induces DNA repair deficiencies by impairing
the homologous recombination repair and base excision repair
pathways. It also affects the cellular stress response by altering
the ATR/ATM kinase pathway, compromising the cell's ability to
manage DNA damage. These defects exacerbate genomic instability and
transcriptional dysregulation, further contributing to tumor
progression. The H3K27M mutation alters m6A methylation and FTO
activity, making DMG cells sensitive to FTO inhibition, which
disrupts cell cycle gene expression and induces apoptosis.
Furthermore, the CHD2/FOSL1 axis plays a crucial role in abnormal
synaptic interactions between neurons and tumor cells, enhancing
tumor growth and invasion by promoting excessive neuronal-tumor
connectivity. Figure created using BioRender.com. H3K27, histone H3
lysine 27, H3K27me3, H3K27 trimethylation; PRC2, polycomb
repressive complex 2; mTOR, mammalian target of rapamycin; FTO,
fat-mass- and obesity-associated protein; DMG, diffuse midline
gliomas.

Figure 2

Mechanisms of targeted therapy in
diffuse midline glioma. (A) ClpP agonist ONC-201 hyperactivates
mitochondrial protease ClpP, leading to respiratory chain protein
degradation, electron transport chain disruption, OXPHOS inhibition
and reduced ATP production. (B) HDAC inhibitor panobinostat
restores p53 function through MDM2/MDM4 modulation and enhanced p53
acetylation, upregulating pro-apoptotic Bax while downregulating
anti-apoptotic Bcl-2 to induce tumor cell apoptosis. (C) CDK4/6
inhibitor ribociclib blocks CDK4/6-cyclin D interaction, inducing
G1 arrest; mTOR inhibitor everolimus suppresses
PI3K/AKT/mTOR signaling to inhibit proliferation and metabolism.
(D) Anti-EGFR antibody nimotuzumab blocks EGF/TGF-α binding,
inhibiting downstream tyrosine kinase signaling and
HIF-1α/VEGF-mediated angiogenesis. Figure created using
BioRender.com. ClpP, caseinolytic protease P; HDAC, histone
deacetylase; mTOR, mammalian target of rapamycin; EGFR, epidermal
growth factor receptor; HIF-1α, hypoxia-inducible factor
1-alpha.
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Spandidos Publications style
Wu W, Chen W, Ma W and Wang Y: <p>Epigenetic mechanisms and therapeutic advances in diffuse midline glioma (Review)</p>. Oncol Rep 55: 50, 2026.
APA
Wu, W., Chen, W., Ma, W., & Wang, Y. (2026). <p>Epigenetic mechanisms and therapeutic advances in diffuse midline glioma (Review)</p>. Oncology Reports, 55, 50. https://doi.org/10.3892/or.2026.9055
MLA
Wu, W., Chen, W., Ma, W., Wang, Y."<p>Epigenetic mechanisms and therapeutic advances in diffuse midline glioma (Review)</p>". Oncology Reports 55.3 (2026): 50.
Chicago
Wu, W., Chen, W., Ma, W., Wang, Y."<p>Epigenetic mechanisms and therapeutic advances in diffuse midline glioma (Review)</p>". Oncology Reports 55, no. 3 (2026): 50. https://doi.org/10.3892/or.2026.9055
Copy and paste a formatted citation
x
Spandidos Publications style
Wu W, Chen W, Ma W and Wang Y: <p>Epigenetic mechanisms and therapeutic advances in diffuse midline glioma (Review)</p>. Oncol Rep 55: 50, 2026.
APA
Wu, W., Chen, W., Ma, W., & Wang, Y. (2026). <p>Epigenetic mechanisms and therapeutic advances in diffuse midline glioma (Review)</p>. Oncology Reports, 55, 50. https://doi.org/10.3892/or.2026.9055
MLA
Wu, W., Chen, W., Ma, W., Wang, Y."<p>Epigenetic mechanisms and therapeutic advances in diffuse midline glioma (Review)</p>". Oncology Reports 55.3 (2026): 50.
Chicago
Wu, W., Chen, W., Ma, W., Wang, Y."<p>Epigenetic mechanisms and therapeutic advances in diffuse midline glioma (Review)</p>". Oncology Reports 55, no. 3 (2026): 50. https://doi.org/10.3892/or.2026.9055
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