Histone deacetylases (HDACs) in XPC gene silencing and bladder cancer

Xiaoxin S Xu,Judith Abrams,Le Wang,Gan Wang

doi:10.1186/1756-8722-4-17

Xiaoxin S Xu, Judith Abrams + Show 2 more

Open Access

https://doi.org/10.1186/1756-8722-4-17

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Abstract

Bladder cancer is one of the most common malignancies and causes hundreds of thousands of deaths 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 inhibition study revealed that the treatment of HTB4 and HTB9 bladder cancer cells with the 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 binding of both CREB1 and Sp1 transcription factors at the promoter region of the XPC gene for both HTB4 and HTB9 cells. The results of our immunohistochemistry (IHC) staining studies further revealed a strong correlation between the over-expression of HDAC4 and increased bladder cancer occurrence (p < 0.001) as well as a marginal significance of increasing incidence of HDAC4 positivity seen with an increase in severity of bladder cancer (p = 0.08). In addition, the results of our caspase 3 activation studies demonstrated that prior treatment with VPA increased the anticancer drug cisplatin-induced activation of caspase 3 in both HTB4 and HTB9 cells. All of these results suggest that the HDACs negatively regulate transcription of the XPC gene in bladder cancer cells and contribute to the severity of bladder tumors.

Highlights

Bladder cancer is one of the most common malignancies
Induced transcription of XPC gene in the valproic acid (VPA)-treated HTB4 and HTB9 bladder cancer cells In order to determine the role that the histone deacetylases (HDACs) may play in XPC gene silencing and bladder cancer development, we first determined the effect of HDAC inhibitor treatment on activation of XPC gene transcription in HTB4 and HTB9 bladder cancer cells
The level of the XPA mRNA was not significantly altered in these cells following the VPA treatment (Table 2). These results suggest that the HDACs play an important role in XPC gene silencing for both HTB4 and HTB9 bladder cancer cells, and treatment with the VPA HDAC inhibitor causes activation of the XPC transcription in both bladder cancer cell lines

Summary

Introduction

Bladder cancer is one of the most common malignancies. More than 350,000 new cases of bladder cancer are diagnosed each year with over 145,000 deaths resulting from the disease [1]. Bladder cancer is strongly associated with exposure to environmental factors. Cigarette smoking is the single most important environmental factor in causing bladder cancer [2]. Exposure to other environmental factors, especially polycyclic aromatic amines, such as aniline, benzidine, and turoline, is closely correlated with bladder cancer risk [2]. The mechanism by which the exposure to environmental factors causes development of bladder cancer is unknown. It is believed that the exposure to the environment makes the bladder tissue more

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