Frontiers in Biomedical Research Abstract_2011 Severson


Paul L. Severson1, Erik J. Tokar2, Lukas Vrba3, Michael P. Waalkes2, Bernard W. Futscher1,3. 1Department
of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, 2National
Toxicology Program Laboratory, National Institute of Environmental Health Sciences, Research Triangle
Park, North Carolina, 3Arizona Cancer Center, University of Arizona, Tucson, Arizona

Millions of people throughout the world are exposed to elevated levels of environmental arsenic which
is associated with many diverse chronic diseases such as cardiovascular disease, neurotoxicity,
immunotoxicity and cancers of the lung, skin, prostate and bladder. In culture, long-term exposure to
arsenicals can induce malignant transformation of immortalized urothelial and prostate epithelial cells
which is accompanied by widespread DNA methylation changes. Epigenetic dysfunction is known to
play an important role in the genesis of all cancers and recent studies have discovered large regions of
the epigenome that undergo long range epigenetic silencing (LRES). Our aim is to characterize the
epigenetic effects of arsenic by determining whether arsenic induced epigenetic changes… 1) are
shared in distinct target tissues, 2) are arsenic specific and 3) contribute to LRES. To this end, we
compared immortalized urothelial and prostate epithelial cells to their arsenic transformed counterparts
using methyl-DNA immunoprecipitations coupled to human promoter microarrays. Similar genomic
locations in both target tissues become hypermethylated in a non-random fashion. A significant portion
of the hypermethylation events are also found in bladder tumors. In the arsenic transformed prostate
epithelial cell line, 12.5kb of DNA within the protocadherin cluster is hypermethylated. This is consistent
with previous reports of LRES at the protocadherin cluster in Wilms’ tumors and breast cancers.
Additional genes such as EN1 and HOXD11 are also within known regions of LRES and become
hypermethylated in the malignant prostate cells. Arsenic transformed urothelial cells also display DNA
hypermethylation in the HOXD cluster, which contains ~7kb of hypermethylated DNA. These data
indicate that chronic arsenic exposure causes hypermethylation of conserved genomic regions and
contributes to LRES which suggests that silencing these regions may play an important role in malignant

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