ArticlePloS one2014
Histone deacetylase inhibitors selectively target homology dependent DNA repair defective cells and elevate non-homologous endjoining activity.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
- Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy.PLoS pathogens · 2014Trial
- Assessing the Effect of Histone Deacetylase Inhibitors on DNA Double-Strand Break Repair by Nonhomologous End Joining.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Chloroquine-Induced DNA Damage Synergizes with Nonhomologous End Joining Inhibition to Cause Ovarian Cancer Cell Cytotoxicity.International journal of molecular sciences · 2022Article
- Trichostatin A enhances radiosensitivity and radiation-induced DNA damage of esophageal cancer cells.Journal of gastrointestinal oncology · 2021Article
- Dynamics and competition of CRISPR-Cas9 ribonucleoproteins and AAV donor-mediated NHEJ, MMEJ and HDR editing.Nucleic acids research · 2021Article
- Genome-Protecting Compounds as Potential Geroprotectors.International journal of molecular sciences · 2020Review
- The prognosis comparison of different molecular subtypes of breast tumors after radiotherapy and the intrinsic reasons for their distinct radiosensitivity.Cancer management and research · 2019Review
- Valproic acid causes radiosensitivity of breast cancer cellsToxicology research · 2016Article
- Knockdown of Rad9A enhanced DNA damage induced by trichostatin A in esophageal cancer cells.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Article
- Downregulation of growth differentiation factor-15 in trichostatin A-induced apoptosis could play a role in progression of gastric cancer.International journal of clinical and experimental pathology · 2015Article
- Histone deacetylase inhibitor induces the expression of select epithelial genes in mouse utricle sensory epithelia-derived progenitor cells.Cellular reprogramming · 2014Article
- Differential expression of glycoprotein non-metastatic melanoma protein B (GPNMB) involved in trichostatin A-induced apoptosis in gastric cancer.International journal of clinical and experimental medicine · 2014Article
Corrections and comments
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Authors and funding
15 authors at 8 institutions in 3 countries.
Funding
Abstract
backgroundWe have previously used the ATAD5-luciferase high-throughput screening assay to identify genotoxic compounds with potential chemotherapeutic capabilities. The successful identification of known genotoxic agents, including the histone deacetylase inhibitor (HDACi) trichostatin A (TSA), confirmed the specificity of the screen since TSA has been widely studied for its ability to cause apoptosis in cancer cells. Because many cancers have acquired mutations in DNA damage checkpoints or repair pathways, we hypothesized that these cancers may be susceptible to treatments that target compensatory pathways. Here, we used a panel of isogenic chicken DT40 B lymphocyte mutant and human cell lines to investigate the ability of TSA to define selective pathways that promote HDACi toxicity.
resultsHDACi induced a DNA damage response and reduced viability in all repair deficient DT40 mutants although ATM-nulls were least affected. The most dramatic sensitivity was observed in mutants lacking the homology dependent repair (HDR) factor BLM or the non-homologous end-joining (NHEJ) and HDR factors, KU/RAD54, suggesting an involvement of either HDR or NHEJ in HDACi-induced cell death. To extend these findings, we measured the frequencies of HDR and NHEJ after HDACi treatment and monitored viability in human cell lines comparably deficient in HDR or NHEJ. Although no difference in HDR frequency was observed between HDACi treated and untreated cells, HDR-defective human cell lines were clearly more sensitive than wild type. Unexpectedly, cells treated with HDACis showed a significantly elevated NHEJ frequency.
conclusionsHDACi targeting drugs induced significant increases in NHEJ activity in human cell lines but did not alter HDR frequency. Moreover, HDR is required for cellular resistance to HDACi therapy; therefore, NHEJ does not appear to be a critical axis for HDACi resistance. Rather, HDACi compounds induced DNA damage, most likely double strand breaks (DSBs), and HDR proficiency is correlated with cell survival.
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