{"doi":"10.1101/2025.06.20.660786","title":"Transient histone deacetylase inhibition reveals cell type invariant and specific effects of chromatin decondensation on irradiation response","abstract":"Abstract Radiation therapy plays a prominent role in breast cancer treatment, but the high doses of radiation damage both healthy and cancerous cells. Therefore, additional research is needed into combination therapies that could preferentially radiosensitize cancer cells compared to surrounding healthy tissue without causing deleterious side effects. Histone deacetylase inhibitor drugs (HDACis) have been tested as radiosensitizers in both basic research and clinical trials, but the long exposure time typically used in these treatments and the lack of matched healthy cell controls often leave aspects of their mechanism of action unclear. Here, we show that transient (2 hour) trichostatin A (TSA) treatment of cancerous and non-tumorigenic breast epithelial cell lines increases immediate DNA damage and decreases long term cell viability in both cell types at high radiation doses. Transient TSA treatment also causes an increase in DNA damage signals after 5 Gy in other cancer and healthy cell types: A375 melanoma cells and BJ5-ta fibroblasts. This suggests that chromatin decompaction acts to increase cellular vulnerability to initial DNA damage from high doses of radiation DNA damage in a cell type independent manner that does not rely on changes to DNA repair pathways caused by longer TSA treatment. However, responses to lower doses of radiation and long term survival are more cell type specific: only MCF7 cells experience an effect of TSA on DNA damage after 1 Gy radiation while MCF10a cells experience somewhat more evident cell viability effects of combined TSA and radiation treatment long term. Scope statement: This manuscript covers several topics that are core to the mission of Frontiers in Cell and Developmental Biology, including cancer cell biology as compared to non-cancerous cell function, cell death vs. survival, and epigenetics and chromosome structure. While some of the implications of this work touch on cancer therapeutics, the study itself focuses on the basics of the interplay between genome architecture and DNA damage and cellular survival / response. We noted several recent articles on related topics in this journal, including the effects of combination treatments on cancer cells (doi 10.3389/fcell.2025.1636288), radiotherapy effects on cells (doi 10.3389/fcell.2025.1568634), and DNA damage (doi 10.3389/fcell.2025.1575483). Our work is well suited for a Brief Research Report as it provides key but focused data on comparisons of radiosensitivity in response to transient chromatin decompaction in cancer vs. healthy cells.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":569070,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9599,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1474101,"name":"Campbell Maben","orcid":null,"position":1,"is_corresponding":false},{"id":419825,"name":"Debjani Pal","orcid":"0000-0002-5870-0005","position":2,"is_corresponding":false},{"id":668228,"name":"Sandra Davern","orcid":"0000-0003-2755-8912","position":4,"is_corresponding":false},{"id":267934,"name":"Rachel Patton McCord","orcid":"0000-0003-0010-5323","position":5,"is_corresponding":false},{"id":976644,"name":"Heng Li","orcid":"0009-0008-7241-3927","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:56:55.795846Z","pmid":"40666972","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}