Abstract 5448: Common targets of epigenetic dysfunction in distinct target tissues of arsenic and cadmium induced malignant transformation

Abstract

Abstract Arsenic and cadmium are known human carcinogens and rank as number one and seven respectively on the Agency for Toxic Substances and Disease Registry (ATSDR) substance priority list. Accumulating evidence suggests that long-term exposure to arsenic or cadmium induces epigenetic dysfunction and this effect may be an important aspect of their carcinogenic activity. To this end we analyzed the epigenetic dysfunction associated with arsenic or cadmium induced malignant transformation of immortalized urothelial and prostate epithelial cells. Using methyl-DNA immunoprecipitations coupled to human promoter microarrays as well as Sequenom MassArray, we found that arsenic and cadmium mediated malignant transformation of immortalized urothelial and prostate epithelial cells produced thousands of DNA methylation changes. Many of the DNA hypermethylation events appear to be localized to individual genes whereas others cluster into groups that are within large genomic regions on the order of 100kb. Significant aggregates of DNA hypermethylation events occur within the protocadherin and HOX gene clusters. Intersecting the arsenic induced hypermethylation events from the two distinct models results in an overlap of 113kb of DNA which represents roughly 100 genes. This overlap is significantly more than expected by chance, suggesting these genes are targeted for aberrant DNA methylation in both models of arsenic induced malignant transformation. A similar result is seen in the cell lines transformed by cadmium, and the cadmium induced DNA hypermethylation events are highly concordant with the hypermethylation profiles induced by arsenic. Most of the DNA hypermethylated regions found in the arsenic or cadmium transformed cells are also targets of aberrant DNA hypermethylation in human bladder tumors. Comparing the hypermethylated regions from our models to publicly available H3K27me3 ChIP-seq data from embryonic stem cells revealed that the targets of DNA hypermethylation fall disproportionately within H3K27me3 domains of human stem cells. H3K27me3 chromatin immunoprecipitations coupled to real-time PCR confirmed that the promoters of candidate genes NPR3 and LTK are marked with H3K27me3 in normal and immortalized cells before becoming DNA hypermethylated in the arsenic transformed cells. This H3K27me3 data supports the previously discovered association between H3K27me3 marked regions of normal cells and DNA hypermethylation in malignant cells. All together, these observations suggest commonality in the mechanisms of epigenetic change induced by carcinogenic metals. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5448. doi:1538-7445.AM2012-5448