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

Xu XS, Wang L, Abrams J, Wang G - J Hematol Oncol (2011)

Bottom Line: Bladder cancer is strongly associated with exposure to environmental carcinogens.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Environmental Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA.

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.

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Immunohistochemistry (IHC) stain of XPC and HDAC4 proteins in both normal and cancerous bladder tissue specimens using bladder tumor tissue arrays. The bladder tumor tissue arrays purchased from US BioMax Inc. were stained with either XPC or HDAC4 antibodies in an immunohistochemistry (IHC) protocol. The presence of XPC or HDAC4 protein was determined by light microscopy and the image was recorded by a DP Controller software (Olympus Corp., Center Valley, PA).
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Figure 3: Immunohistochemistry (IHC) stain of XPC and HDAC4 proteins in both normal and cancerous bladder tissue specimens using bladder tumor tissue arrays. The bladder tumor tissue arrays purchased from US BioMax Inc. were stained with either XPC or HDAC4 antibodies in an immunohistochemistry (IHC) protocol. The presence of XPC or HDAC4 protein was determined by light microscopy and the image was recorded by a DP Controller software (Olympus Corp., Center Valley, PA).

Mentions: To further determine the role of HDACs in XPC gene silencing and bladder cancer development, we determined the correlation between the presence of HDACs and the occurrence of bladder cancer using bladder tumor tissue arrays with an immunohistochemistry (IHC) staining procedure (Figure 3 and Table 4). The bladder tumor tissue arrays were purchased from US BioMax, Inc. (Rockville, MD) and used in this study. Both HDAC2 and HDAC4 were chosen for this study because the work of others has revealed abnormal levels of these proteins in many types of cancer [47-55]. The results of our IHC study indicated that the frequency of the HDAC4-positive tissue specimens was much higher in the bladder tumors than in the normal bladder tissues (Figure 3 panel and Table 4). The statistical analysis of the data further revealed a significant difference in the frequency of HDAC4-positive tissue specimens between normal and cancerous bladder tissues (p < 0.001) as well as a marginal significance between the increasing incidence of HDAC4 positivity and the increasing severity of the bladder tumors (p = 0.08) (Table 4). The frequency of the HDAC2-positive specimens, however, was similar between normal and cancerous bladder tissues (data not shown). These results suggest that over-expression of the HDAC4 is strongly correlated with the development of bladder cancer.


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

Xu XS, Wang L, Abrams J, Wang G - J Hematol Oncol (2011)

Immunohistochemistry (IHC) stain of XPC and HDAC4 proteins in both normal and cancerous bladder tissue specimens using bladder tumor tissue arrays. The bladder tumor tissue arrays purchased from US BioMax Inc. were stained with either XPC or HDAC4 antibodies in an immunohistochemistry (IHC) protocol. The presence of XPC or HDAC4 protein was determined by light microscopy and the image was recorded by a DP Controller software (Olympus Corp., Center Valley, PA).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108377&req=5

Figure 3: Immunohistochemistry (IHC) stain of XPC and HDAC4 proteins in both normal and cancerous bladder tissue specimens using bladder tumor tissue arrays. The bladder tumor tissue arrays purchased from US BioMax Inc. were stained with either XPC or HDAC4 antibodies in an immunohistochemistry (IHC) protocol. The presence of XPC or HDAC4 protein was determined by light microscopy and the image was recorded by a DP Controller software (Olympus Corp., Center Valley, PA).
Mentions: To further determine the role of HDACs in XPC gene silencing and bladder cancer development, we determined the correlation between the presence of HDACs and the occurrence of bladder cancer using bladder tumor tissue arrays with an immunohistochemistry (IHC) staining procedure (Figure 3 and Table 4). The bladder tumor tissue arrays were purchased from US BioMax, Inc. (Rockville, MD) and used in this study. Both HDAC2 and HDAC4 were chosen for this study because the work of others has revealed abnormal levels of these proteins in many types of cancer [47-55]. The results of our IHC study indicated that the frequency of the HDAC4-positive tissue specimens was much higher in the bladder tumors than in the normal bladder tissues (Figure 3 panel and Table 4). The statistical analysis of the data further revealed a significant difference in the frequency of HDAC4-positive tissue specimens between normal and cancerous bladder tissues (p < 0.001) as well as a marginal significance between the increasing incidence of HDAC4 positivity and the increasing severity of the bladder tumors (p = 0.08) (Table 4). The frequency of the HDAC2-positive specimens, however, was similar between normal and cancerous bladder tissues (data not shown). These results suggest that over-expression of the HDAC4 is strongly correlated with the development of bladder cancer.

Bottom Line: Bladder cancer is strongly associated with exposure to environmental carcinogens.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Environmental Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA.

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.

Show MeSH
Related in: MedlinePlus