journal contribution
posted on 2023-04-03, 20:03 authored by Jonathan Dow, Adam Krysztofiak, Yanfeng Liu, Daniel A. Colon-Rios, Faye A. Rogers, Peter M. Glazer SFig 1: SAHA reduces H3K9 trimethylation in IDH1 mutant cells while increasing H3K9 and H4 acetylation, SFig 2: Characterization of U2OS EJDR cells after SAHA, metabolite and siRNA treatment, SFig 3: SAHA elevates DNA damage to a greater degree in IDH1 mutant cells, comparable to BRCA1 and RAD51 siRNA knockdown, SFig 4: SAHA represses RAD51 and increases γ-H2AX foci formation, SFig 5: Mutant IDH1 sensitivity to PARPi treatment, SFig 6: Synergy of SAHA combination with radiation, TMZ and PARPi, SFig 7: SAHA down-regulates HDR factor expression, elevates DNA damage and has greater effect alone and plus PARPi against IDH1 mutant HCT116 cells
Funding
NIH
National Institute of General Medical Science
History
ARTICLE ABSTRACT
Exploitation of DNA repair defects has enabled major advances in treating specific cancers. Recent work discovered that the oncometabolite 2-hydroxyglutarate (2-HG), produced by neomorphic isocitrate dehydrogenase 1/2 (IDH1/2) mutations, confers a homology-directed repair (HDR) defect through 2-HG–induced histone hypermethylation masking HDR signaling. Here, we report that IDH1-mutant cancer cells are profoundly sensitive to the histone deacetylase inhibitor (HDACi) vorinostat, by further suppressing the residual HDR in 2-HG–producing cells. Vorinostat downregulates repair factors BRCA1 and RAD51 via disrupted E2F-factor regulation, causing increased DNA double-strand breaks, reduced DNA repair factor foci, and functional HDR deficiency even beyond 2-HG's effects. This results in greater cell death of IDH1-mutant cells and confers synergy with radiation and PARPi, both against cells in culture and patient-derived tumor xenografts. Our work identifies HDACi's utility against IDH1-mutant cancers, and presents IDH1/2 mutations as potential biomarkers to guide trials testing HDACi in gliomas and other malignancies.
IDH1-mutant cells show profound vulnerability to HDACi treatment, alone and with PARPi and radiation, via HDR suppression, presenting IDH1/2 mutations as biomarkers for HDACi use in gliomas and other malignancies.
