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Cell Dev. Biol."],"abstract":"<jats:p>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\u00a0h) 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\u00a0Gy X-rays 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 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\u00a0Gy X-ray radiation while MCF10a cells experience somewhat more evident cell viability effects of combined TSA and radiation treatment long term.<\/jats:p>","DOI":"10.3389\/fcell.2026.1691057","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T05:41:03Z","timestamp":1788154863000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Transient histone deacetylase inhibition reveals cell type invariant and specific effects of chromatin decondensation on irradiation response"],"prefix":"10.3389","volume":"14","author":[{"given":"Heng","family":"Li","sequence":"first","affiliation":[{"name":"Biochemistry & Cellular and Molecular Biology, University of Tennessee","place":["Knoxville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Campbell","family":"Maben","sequence":"additional","affiliation":[{"name":"Biochemistry & Cellular and Molecular Biology, University of Tennessee","place":["Knoxville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey","family":"Young","sequence":"additional","affiliation":[{"name":"Biochemistry & Cellular and Molecular Biology, University of Tennessee","place":["Knoxville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debjani","family":"Pal","sequence":"additional","affiliation":[{"name":"Radioisotope Research and Development Section, Oak Ridge National Laboratory","place":["Oak Ridge, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Davern","sequence":"additional","affiliation":[{"name":"Radioisotope Research and Development Section, Oak Ridge National Laboratory","place":["Oak Ridge, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel Patton","family":"McCord","sequence":"additional","affiliation":[{"name":"Biochemistry & Cellular and Molecular Biology, University of Tennessee","place":["Knoxville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"8094","DOI":"10.1158\/1078-0432.CCR-04-1023","article-title":"Histone deacetylase inhibitor trichostatin A represses estrogen receptor \u03b1-Dependent transcription and promotes proteasomal degradation of cyclin D1 in human breast carcinoma cell lines","volume":"10","author":"Alao","year":"2004","journal-title":"Clin. 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