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Carcinogenesis Advance Access published online on April 30, 2008
Carcinogenesis, doi:10.1093/carcin/bgn102
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Epigenetic Remodeling During Arsenical-Induced Malignant Transformation

Taylor J. Jensen1,2, Petr Novak2,3, Kylee E. Eblin1, A. Jay Gandolfi1 and Bernard W. Futscher1,2

1 Department of Pharmacology and Toxicology, College of Pharmacy
2 Arizona Cancer Center, University of Arizona, Tucson, Arizona, 85724, USA
3 Institute of Plant Molecular Biology AS CR, Ceske Budejovice 37005, Czech Republic

Corresponding Author Address: Bernard W. Futscher, Ph.D., 1515 N. Campbell, Levy Bldg 3925, Tucson, AZ, 85724. Tel.: (520) 626-4646. Fax: (520) 626-5462. Email: bfutscher{at}azcc.arizona.edu

Humans are exposed to arsenicals through many routes with the most common being in drinking water. Exposure to arsenic has been associated with an increase in the incidence of cancer of the skin, lung, and bladder. Although the relationship between exposure and carcinogenesis is well documented, the mechanisms by which arsenic participates in tumorigenesis are not fully elucidated. We evaluated the potential epigenetic component of arsenical action by assessing the histone acetylation state of 13,000 human gene promoters in a cell line model of arsenical-mediated malignant transformation. We show changes in histone H3 acetylation occur during arsenical-induced malignant transformation that are linked to the expression state of the associated gene. DNA hypermethylation was detected in hypoacetylated promoters in the select cases analyzed. These epigenetic changes occurred frequently in the same promoters whether the selection was performed with arsenite [As(III)] or with monomethylarsonous acid [MMA(III)], suggesting that these promoters were targeted in a nonrandom fashion, and likely occur in regions important in arsenical-induced malignant transformation. Taken together, these data suggest that arsenicals may participate in tumorigenesis by altering the epigenetic terrain of select genes.

Received February 15, 2008; revised April 3, 2008; accepted April 14, 2008.


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