{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:06:29Z","timestamp":1791821189404,"version":"4.3.4"},"reference-count":22,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T00:00:00Z","timestamp":1687219200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Polish National Science Center","award":["2016\/22\/M\/NZ7\/00375"],"award-info":[{"award-number":["2016\/22\/M\/NZ7\/00375"]}]},{"name":"Polish National Science Center","award":["POWR.03.02.00-00-I033\/16-00)"],"award-info":[{"award-number":["POWR.03.02.00-00-I033\/16-00)"]}]},{"DOI":"10.13039\/501100004895","name":"European Social Fund","doi-asserted-by":"publisher","award":["2016\/22\/M\/NZ7\/00375"],"award-info":[{"award-number":["2016\/22\/M\/NZ7\/00375"]}],"id":[{"id":"10.13039\/501100004895","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004895","name":"European Social Fund","doi-asserted-by":"publisher","award":["POWR.03.02.00-00-I033\/16-00)"],"award-info":[{"award-number":["POWR.03.02.00-00-I033\/16-00)"]}],"id":[{"id":"10.13039\/501100004895","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The inhibition of histone deacetylases (HDACs) holds promise as a potential anti-cancer therapy as histone and non-histone protein acetylation is frequently disrupted in cancer, leading to cancer initiation and progression. Additionally, the use of a histone deacetylase inhibitor (HDACi) such as the class I HDAC inhibitor\u2014valproic acid (VPA) has been shown to enhance the effectiveness of DNA-damaging factors, such as cisplatin or radiation. In this study, we found that the use of VPA in combination with talazoparib (BMN-673\u2014PARP1 inhibitor\u2014PARPi) and\/or Dacarbazine (DTIC\u2014alkylating agent) resulted in an increased rate of DNA double strand breaks (DSBs) and reduced survival (while not affecting primary melanocytes) and the proliferation of melanoma cells. Furthermore, the pharmacological inhibition of class I HDACs sensitizes melanoma cells to apoptosis following exposure to DTIC and BMN-673. In addition, the inhibition of HDACs causes the sensitization of melanoma cells to DTIV and BMN-673 in melanoma xenografts in vivo. At the mRNA and protein level, the histone deacetylase inhibitor downregulated RAD51 and FANCD2. This study aims to demonstrate that combining an HDACi, alkylating agent and PARPi could potentially enhance the treatment of melanoma, which is commonly recognized as being among the most aggressive malignant tumors. The findings presented here point to a scenario in which HDACs, via enhancing the HR-dependent repair of DSBs created during the processing of DNA lesions, are essential nodes in the resistance of malignant melanoma cells to methylating agent-based therapies.<\/jats:p>","DOI":"10.3390\/genes14061295","type":"journal-article","created":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T01:37:38Z","timestamp":1687225058000},"page":"1295","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Histone Deacetylases (HDAC) Inhibitor\u2014Valproic Acid Sensitizes Human Melanoma Cells to Dacarbazine and PARP Inhibitor"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5869-7993","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Drzewiecka","sequence":"first","affiliation":[{"name":"Laboratory of Medical Genetics Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6159-4194","authenticated-orcid":false,"given":"Anna","family":"Gajos-Michniewicz","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology of Cancer, Medical University of Lodz, 92-215 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0917-5611","authenticated-orcid":false,"given":"Gra\u017cyna","family":"Hoser","sequence":"additional","affiliation":[{"name":"Department of Flow Cytometry, Medical Center for Postgraduate Education, 01-813 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominika","family":"Ja\u015bniak","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Barszczewska-Pietraszek","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5495-3550","authenticated-orcid":false,"given":"Przemys\u0142aw","family":"Sitarek","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Medical University of Lodz, ul. Muszy\u0144skiego 1, 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5146-5225","authenticated-orcid":false,"given":"Piotr","family":"Czarny","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Medical University of Lodz, 92-216 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janusz","family":"Piekarski","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, Medical University of Lodz, 90-419 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3544-1482","authenticated-orcid":false,"given":"Maciej","family":"Radek","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Surgery of Spine and Peripheral Nerves, Medical University of Lodz, University Hospital WAM-CSW, 90-549 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8279-4742","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Czy\u017c","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology of Cancer, Medical University of Lodz, 92-215 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Skorski","sequence":"additional","affiliation":[{"name":"Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8385-7744","authenticated-orcid":false,"given":"Tomasz","family":"\u015aliwi\u0144ski","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3067","DOI":"10.1158\/0008-5472.CAN-15-2680","article-title":"Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance","volume":"76","author":"Krumm","year":"2016","journal-title":"Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2666","DOI":"10.1158\/2159-8290.CD-22-0111","article-title":"AXL and Error-Prone DNA Replication Confer Drug Resistance and Offer Strategies to Treat EGFR-Mutant Lung Cancer","volume":"12","author":"Noronha","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_3","first-page":"488","article-title":"Treatment of Metastatic Melanoma: An Overview","volume":"23","author":"Bhatia","year":"2010","journal-title":"Oncology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0305-7372(97)90019-0","article-title":"Temozolomide: A Review of Its Discovery, Chemical Properties, Pre-Clinical Development and Clinical Trials","volume":"23","author":"Newlands","year":"1997","journal-title":"Cancer Treat. 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