Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance.

Abstract

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.

• Authors: Andrea Krumm, Christina Barckhausen, Pelin Kücük, Karl-Heinz Tomaszowski, Carmen Loquai, Jörg Fahrer, Oliver Holger Krämer, Bernd Kaina, Wynand Paul Roos
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 10 Pg. 3067-77 (05 15 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 26980768 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• FANCD2 protein, human
• Fanconi Anemia Complementation Group D2 Protein
• Histone Deacetylase Inhibitors
• RNA, Messenger
• RAD51 protein, human
• Rad51 Recombinase
• Histone Deacetylases

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Cell Proliferation (drug effects)
• DNA Breaks, Double-Stranded (drug effects)
• DNA Repair (drug effects)
• Drug Resistance, Neoplasm
• Fanconi Anemia Complementation Group D2 Protein (antagonists & inhibitors, genetics, metabolism)
• Fluorescent Antibody Technique
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (chemistry, genetics, metabolism)
• Homologous Recombination (drug effects)
• Humans
• Immunoenzyme Techniques
• Melanoma (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• RNA, Messenger (genetics)
• Rad51 Recombinase (antagonists & inhibitors, genetics, metabolism)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Skin (drug effects, metabolism, pathology)
• Skin Neoplasms (drug therapy, metabolism, pathology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• Melanoma, Cutaneous Malignant