IDH1 mutant glioma is preferentially sensitive to the HDAC inhibitor panobinostat.

Abstract

INTRODUCTION:

A large subset of diffusely infiltrative gliomas contains a gain-of-function mutation in isocitrate dehydrogenase 1 or 2 (IDH1/2mut) which produces 2-hydroxglutarate, an inhibitor of α-ketoglutarate-dependent DNA demethylases, thereby inducing widespread DNA and histone methylation. Because histone deacetylase (HDAC) enzymes are localized to methylated chromatin via methyl-binding domain proteins, IDH1/2mut gliomas may be more dependent on HDAC activity, and therefore may be more sensitive to HDAC inhibitors.

METHODS:

Six cultured patient-derived glioma cell lines, IDH1wt (n = 3) and IDH1mut (n = 3), were treated with an FDA-approved HDAC inhibitor, panobinostat. Cellular cytotoxicity and proliferation assays were conducted by flow cytometry. Histone modifications and cell signaling pathways were assessed using immunoblot and/or ELISA.

RESULTS:

IDH1mut gliomas exhibited marked upregulation of genes associated with the HDAC activity. Glioma cell cultures bearing IDH1mut were significantly more sensitive to the cytotoxic and antiproliferative effects of panobinostat, compared to IDH1wt glioma cells. Panobinostat caused a greater increase in acetylation of the histone residues H3K14, H3K18, and H3K27 in IDH1mut glioma cells. Another HDAC inhibitor, valproic acid, was also more effective against IDH1mut glioma cells.

CONCLUSION:

These data suggest that IDH1mut gliomas may be preferentially sensitive to HDAC inhibitors. Further, IDH1mut glioma cultures showed enhanced accumulation of acetylated histone residues in response to panobinostat treatment, suggesting a direct epigenetic mechanism for this sensitivity. This provides a rationale for further exploration of HDAC inhibitors against IDH1mut gliomas.

• Authors: Thomas K Sears, Craig M Horbinski, Kevin D Woolard
• Journal: Journal of neuro-oncology (J Neurooncol) Vol. 154 Issue 2 Pg. 159-170 (Sep 2021) ISSN: 1573-7373 [Electronic] United States
• PMID: 34424450 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• Histone Deacetylase Inhibitors
• Histones
• Panobinostat
• Isocitrate Dehydrogenase
• IDH1 protein, human

Topics

• Glioma (drug therapy, genetics)
• Histone Deacetylase Inhibitors (pharmacology)
• Histones
• Humans
• Isocitrate Dehydrogenase (genetics, metabolism)
• Mutation
• Panobinostat (pharmacology)