Abstract 4861: The role of histone deacetylases (HDACs) in XPC gene silencing and bladder cancer development

Abstract

Abstract The role of histone deacetylases (HDACs) in XPC gene silencing and bladder cancer development Xiaoxin S. Xu, Le Wang, and Gan Wang Institute of Environmental Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48202 Bladder cancer is one of the most common malignancies and causes hundreds thousands of death worldwide each year. Bladder cancer is strongly associated with exposure to environmental carcinogens. It is believed that DNA damage generated by environmental carcinogens and their metabolites causes development of bladder cancer. Nucleotide excision repair (NER) is the major DNA repair pathway for repairing bulk DNA damage generated by most environmental carcinogens and XPC is a DNA damage recognition protein required for initiation of the NER process. Recent studies demonstrate reduced levels of XPC protein in tumors for a majority of bladder cancer patients. In this work we investigated the role of histone deacetylases (HDACs) in XPC gene silencing and bladder cancer development. The results of our HDAC inhibitor study revealed that the treatment of HTB4 and HTB9 bladder cancer cells with HDAC inhibitor valproic acid (VPA) caused an increase in transcription of the XPC gene in these cells. The results of our chromatin immunoprecipitation (ChIP) studies indicated that the VPA treatment caused increased bindings of both CREB1 and Sp1 transcription factors at the promoter of XPC gene for both HTB4 and HTB9 cells. The results of our immunohistochemistry (IHC) staining studies further revealed a strong correlation between the presence of HDAC4 and the occurrence of bladder tumors. In addition, the results of our caspase 3 activation studies demonstrated that the prior treatment with VPA increased the anticancer drug cisplatin-induced activation of caspase 3 in both HTB4 and HTB9 cells. All these results suggest that the HDACs negatively regulate transcription of the XPC gene in bladder cancer cells and contribute to the development of bladder cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4861.