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Updated: Aug 5, 2026
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Published on: September 13, 2022
Interplay of Epigenetic Reprogramming, Mitochondrial Metabolism, and Dopamine Signalling Pathways Uncovers Metabolic
Han Shen1,2, Yizhou Huang3,4, Kristina M Cook1,2
1Translational Radiation Biology and Oncology Group, Centre for Cancer Research, The Westmead Institute for Medical Research, Westmead, NSW 2145, Australia.
Cancers
|July 28, 2026
Summary
Diffuse midline glioma (DMG), a fatal pediatric brain tumor, is linked to H3K27M mutations. This review explores how epigenetic changes, mitochondrial metabolism, and dopamine signaling create vulnerabilities that ONC201 may exploit for treatment.
Area of Science:
- Neuro-oncology
- Epigenetics
- Cancer Metabolism
Background:
- Diffuse midline glioma (DMG) is a highly aggressive pediatric brain tumor with a poor prognosis.
- The H3K27M mutation is a hallmark of ~80% of DMGs, disrupting PRC2 activity and chromatin structure.
- Emerging evidence links H3K27M-driven epigenetic alterations to significant changes in tumor cell metabolism.
Purpose of the Study:
- To review the interconnected roles of epigenetic dysregulation, mitochondrial metabolism, and dopamine signaling in DMG.
- To propose a hypothesis on how H3K27M mutations influence metabolic dependencies and dopamine's role in mitochondrial homeostasis.
- To highlight potential therapeutic strategies targeting this axis in treatment-resistant DMG.
Main Methods:
- Literature review synthesizing current research on DMG, H3K27M mutations, epigenetics, and metabolism.
- Analysis of studies investigating mitochondrial function, oxidative phosphorylation, and redox regulation in H3K27M-mutant tumors.
- Examination of the role of dopaminergic signaling in cancer stem cell maintenance and metabolic regulation.
Main Results:
- H3K27M mutations are associated with altered mitochondrial metabolism, including oxidative phosphorylation and stress responses, though dependence varies.
- Dopaminergic signaling is implicated in cancer stem cell survival and metabolic regulation across malignancies.
- The compound ONC201/dordaviprone shows clinical activity in H3K27M-mutant DMG by inducing mitochondrial stress.
Conclusions:
- H3K27M-driven epigenetic reprogramming may create metabolic vulnerabilities by increasing reliance on mitochondrial bioenergetics.
- Dopamine signaling might act as a metabolic rheostat, potentially influencing mitochondrial homeostasis in DMG.
- Targeting the interplay between epigenetics, metabolism, and dopamine signaling presents a promising therapeutic avenue for H3K27M-mutant DMG.