Oncohistone interactome profiling uncovers contrasting oncogenic mechanisms and identifies potential therapeutic

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Evaluation of Biomarkers in Glioma by Immunohistochemistry on Paraffin-Embedded 3D Glioma Neurosphere Cultures
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Evaluation of Biomarkers in Glioma by Immunohistochemistry on Paraffin-Embedded 3D Glioma Neurosphere Cultures

Published on: January 9, 2019

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Robert Siddaway1,2,3, Laura Canty1,2, Sanja Pajovic1,2

  • 1The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.

Acta Neuropathologica
|September 7, 2022
PubMed

Insights

Histone H3 mutations drive pediatric glioma. Targeting H3K9 methylation is lethal to these cancer cells, offering a promising therapeutic strategy for oncohistone-mutant gliomas.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Pediatric-type high-grade glioma (pHGG) is driven by histone H3 mutations, specifically H3K27M and H3G34R.
  • H3K27M mutations disrupt H3K27me3 via PRC2 inhibition, while H3G34R mutations cause H3K36me3 loss by inhibiting SETD2.
  • The comprehensive oncogenic mechanisms of these mutations are not fully understood.

Purpose of the Study:

  • To characterize the interactomes of H3.1K27M, H3.3K27M, and H3.3G34R mutants.
  • To elucidate the broader oncogenic mechanisms and identify potential therapeutic targets in oncohistone-mutant gliomas.

Main Methods:

  • Interactome analysis of H3.1K27M, H3.3K27M, and H3.3G34R.
  • Assessment of epigenetic modifications, transcription factor binding, DNA methylation, mitochondrial metabolism, DNA repair interactions, and H3K9 methyltransferase interactions.
  • Investigation of the role of H3K9 methylation in H3K27M-driven global H3K27me3 disruption.
  • Evaluation of H3K9 methyltransferase inhibition as a therapeutic strategy in pHGG cell lines.

Main Results:

  • H3K27M interactome revealed epigenetic and transcription factor alterations.
  • H3G34R interactome showed removal of breaks on cryptic transcription, limited DNA methyltransferase access, and altered mitochondrial metabolism.
  • All three mutants exhibited altered interactions with DNA repair proteins and H3K9 methyltransferases.
  • H3K9me3 was reduced in H3K27M nucleosomes; cis-H3K9 methylation was essential for H3K27M's effect on global H3K27me3.
  • Inhibition of H3K9 methyltransferases was lethal to all tested oncohistone-mutant pHGG cells.

Conclusions:

  • H3K9 methylation is crucial for the survival of oncohistone-mutant gliomas.
  • H3K9 methyltransferase inhibition represents a promising therapeutic target for pediatric-type high-grade glioma.
Keywords:
H3G34RH3K27MH3K9 methylationpHGG

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