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Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance.
Krumm, Andrea; Barckhausen, Christina; Kücük, Pelin; Tomaszowski, Karl-Heinz; Loquai, Carmen; Fahrer, Jörg; Krämer, Oliver Holger; Kaina, Bernd; Roos, Wynand Paul.
Afiliación
  • Krumm A; Institute of Toxicology, Medical Center of the University Mainz, Mainz, Germany.
  • Barckhausen C; Institute of Toxicology, Medical Center of the University Mainz, Mainz, Germany.
  • Kücük P; Institute of Toxicology, Medical Center of the University Mainz, Mainz, Germany.
  • Tomaszowski KH; Institute of Toxicology, Medical Center of the University Mainz, Mainz, Germany.
  • Loquai C; Department of Dermatology, Medical Center of the University Mainz, Mainz, Germany.
  • Fahrer J; Institute of Toxicology, Medical Center of the University Mainz, Mainz, Germany.
  • Krämer OH; Institute of Toxicology, Medical Center of the University Mainz, Mainz, Germany.
  • Kaina B; Institute of Toxicology, Medical Center of the University Mainz, Mainz, Germany.
  • Roos WP; Institute of Toxicology, Medical Center of the University Mainz, Mainz, Germany. rooswy00@uni-mainz.de wynandpaulroos@yahoo.co.uk.
Cancer Res ; 76(10): 3067-77, 2016 05 15.
Article en En | MEDLINE | ID: mdl-26980768
DNA-damaging anticancer drugs remain a part of metastatic melanoma therapy. Epigenetic reprogramming caused by increased histone deacetylase (HDAC) activity arising during tumor formation may contribute to resistance of melanomas to the alkylating drugs temozolomide, dacarbazine, and fotemustine. Here, we report on the impact of class I HDACs on the response of malignant melanoma cells treated with alkylating agents. The data show that malignant melanomas in situ contain a high level of HDAC1/2 and malignant melanoma cells overexpress HDAC1/2/3 compared with noncancer cells. Furthermore, pharmacologic inhibition of class I HDACs sensitizes malignant melanoma cells to apoptosis following exposure to alkylating agents, while not affecting primary melanocytes. Inhibition of HDAC1/2/3 caused sensitization of melanoma cells to temozolomide in vitro and in melanoma xenografts in vivo HDAC1/2/3 inhibition resulted in suppression of DNA double-strand break (DSB) repair by homologous recombination because of downregulation of RAD51 and FANCD2. This sensitized cells to the cytotoxic DNA lesion O(6)-methylguanine and caused a synthetic lethal interaction with the PARP-1 inhibitor olaparib. Furthermore, knockdown experiments identified HDAC2 as being responsible for the regulation of RAD51. The influence of class I HDACs on DSB repair by homologous recombination and the possible clinical implication on malignant melanoma therapy with temozolomide and other alkylating drugs suggests a combination approach where class I HDAC inhibitors such as valproic acid or MS-275 (entinostat) appear to counteract HDAC- and RAD51/FANCD2-mediated melanoma cell resistance. Cancer Res; 76(10); 3067-77. ©2016 AACR.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Cutáneas / Resistencia a Antineoplásicos / Recombinasa Rad51 / Proteína del Grupo de Complementación D2 de la Anemia de Fanconi / Inhibidores de Histona Desacetilasas / Histona Desacetilasas / Melanoma Idioma: En Revista: Cancer Res Año: 2016 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Cutáneas / Resistencia a Antineoplásicos / Recombinasa Rad51 / Proteína del Grupo de Complementación D2 de la Anemia de Fanconi / Inhibidores de Histona Desacetilasas / Histona Desacetilasas / Melanoma Idioma: En Revista: Cancer Res Año: 2016 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos