IDH1 mutant glioma is preferentially sensitive to the HDAC inhibitor panobinostat

Thomas K Sears,Craig M Horbinski,Kevin D Woolard

doi:10.1007/s11060-021-03829-0

Thomas K Sears, Craig M Horbinski + Show 1 more

Open Access

https://doi.org/10.1007/s11060-021-03829-0

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Abstract

IntroductionA 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.MethodsSix 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.ResultsIDH1mut 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.ConclusionThese 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.

Highlights

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
This gradually leads to a global increase in DNA and histone methylation in IDH1/2mut gliomas [3,4,5]
The distinction is so dramatic that the new World Health Organization (WHO) scheme has split adult-type infiltrative gliomas into three discrete subsets: “Astrocytoma, IDH1/2mut, WHO grades 2–4,” “Oligodendroglioma, IDH1/2mut and 1p/19q-codeleted, WHO grades 2–3” and “Glioblastoma, IDH1/2wt, WHO grade 4” [6]

Summary

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. In cell viability dose–response assays, IDH1mut glioma cells were much more sensitive to an FDAapproved pan-HDACi, panobinostat, compared to their IDH1/2wt counterparts, with a 4.1 fold difference in IC50 values (Fig. 2a, b; Fig. S3; Table S2). Annexin V apoptosis dose–response assays showed an even more pronounced sensitivity to panobinostat in IDH1mut cells, with a tenfold difference in average EC50 values compared to IDH1/2wt (Fig. 2c, d; Fig. S4; Table S2).

Results

Conclusion