ArticleMolecular cancer research : MCR2021
Vulnerability of IDH1-Mutant Cancers to Histone Deacetylase Inhibition via Orthogonal Suppression of DNA Repair.
Article in Molecular cancer research : MCR, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 17 citations in OpenAlex.
- SMARCAL1 is a targetable synthetic lethal therapeutic vulnerability in ATRX-deficient gliomas that use alternative lengthening of telomeres.Neuro-oncology · 2026Article
- Time-Resolved Transcriptomic Profiling of Surgical Wounds Identifies Stage-Specific Therapeutic Targets for Residual Ovarian Cancer.Pharmaceutics · 2026Article
- Three-dimensional-bioprinted stiff matrix triggers PDAC radioresistance through histone H3 lysine 18 lactylation (H3K18la) potentiates RAD51 activation.Regenerative biomaterials · 2026Article
- PARP inhibitor resistance in IDH1-mutant cancers due to loss of end protection factors, 53BP1 and REV7.NAR cancer · 2025Article
- TCA cycle-derived oncometabolites in cancer and the immune microenvironment.Journal of biomedical science · 2025Review
- Epigenetics: Mechanisms, potential roles, and therapeutic strategies in cancer progression.Genes & diseases · 2024Review
- HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma.Scientific reports · 2023Article
- Mutant Isocitrate Dehydrogenase 1 Expression Enhances Response of Gliomas to the Histone Deacetylase Inhibitor Belinostat.Tomography (Ann Arbor, Mich.) · 2023Article
- Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Accumulation of oncometabolite D-2-Hydroxyglutarate by SLC25A1 inhibition: A metabolic strategy for induction of HR-ness and radiosensitivity.Cell death & disease · 2022Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
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. IMPLICATIONS: 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.
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