DNA Methylation Aberrations in Dimethylarsinic Acid-Induced Bladder Carcinogenesis

SIMPLE SUMMARY: Arsenic is a known carcinogen for the human urinary bladder. The present study explored aberrant DNA methylation in rat bladder carcinogenesis induced by dimethylarsinic acid (DMA(V)), a primary arsenic metabolite. Genome-wide DNA methylation and microarray gene expression analyses of DMA(V)-induced rat urothelial carcinoma (UC) and the urothelium of rats treated with DMA(V) for 4 weeks identified 40 genes that were both hypermethylated and downregulated in DMA(V)-induced rat urothelial carcinoma. Notably, four of these genes (CPXM1, OPCML, TBX20, and KCND3) also showed reduced expression in the bladder urothelium after 4 weeks of exposure to DMA(V). Furthermore, CPXM1 is aberrantly methylated and downregulated in human bladder cancers and human bladder cancer cells. Our findings highlight the significance of aberrant DNA methylation in DMA(V)-induced bladder carcinogenesis, implying early-stage arsenic-induced methylation changes. ABSTRACT: Arsenic is a known human urinary bladder carcinogen. While arsenic is known to cause aberrant DNA methylation, the mechanism of arsenic-triggered bladder carcinogenesis is not fully understood. The goal of this study was to identify aberrant DNA methylation in rat bladder urothelial carcinoma (UC) induced by dimethylarsinic acid (DMA(V)), a major organic metabolite of arsenic. We performed genome-wide DNA methylation and microarray gene expression analyses of DMA(V)-induced rat UCs and the urothelium of rats treated for 4 weeks with DMA(V). We identified 40 genes that were both hypermethylated and downregulated in DMA(V)-induced rat UCs. Notably, four genes (CPXM1, OPCML, TBX20, and KCND3) also showed reduced expression in the bladder urothelium after 4 weeks of exposure to DMA(V). We also found that CPXM1 is aberrantly methylated and downregulated in human bladder cancers and human bladder cancer cells. Genes with aberrant DNA methylation and downregulated expression in DMA(V)-exposed bladder urothelium and in DMA(V)-induced UCs in rats, suggest that these alterations occurred in the early stages of arsenic-induced bladder carcinogenesis. Further study to evaluate the functions of these genes will advance our understanding of the role of aberrant DNA methylation in arsenic bladder carcinogenesis, and will also facilitate the identification of new therapeutic targets for arsenic-related bladder cancers.