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 (IDH1/2^mut) 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, IDH1/2^mut 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, IDH1^wt (n = 3) and IDH1^mut (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

IDH1^mut gliomas exhibited marked upregulation of genes associated with the HDAC activity. Glioma cell cultures bearing IDH1^mut were significantly more sensitive to the cytotoxic and antiproliferative effects of panobinostat, compared to IDH1^wt glioma cells. Panobinostat caused a greater increase in acetylation of the histone residues H3K14, H3K18, and H3K27 in IDH1^mut glioma cells. Another HDAC inhibitor, valproic acid, was also more effective against IDH1^mut glioma cells.

Conclusion

These data suggest that IDH1^mut gliomas may be preferentially sensitive to HDAC inhibitors. Further, IDH1^mut 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 IDH1^mut gliomas.

SUBMITTER: Sears TK 

PROVIDER: S-EPMC8437887 | biostudies-literature |

REPOSITORIES: biostudies-literature