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Carcinogenesis Advance Access published online on March 4, 2008
Carcinogenesis, doi:10.1093/carcin/bgn063
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Arsenite alters global histone H3 methylation

Xue Zhou{dagger}, Hong Sun{dagger}, Thomas P. Ellen, Haobin Chen and Max Costa*

Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, New York 10987, USA

* Corresponding author. Mailing Address: Nelson Institute of Environmental Medicine, NYU Cancer Institute and Department of Pharmacology, New York University School of Medicine, 550 First Ave, New York, NY 10016. Phone: (845) 731-3515 Fax: (845) 351-2118. Email: max.costa{at}nyumc.edu

Arsenic (As) is a well-characterized human carcinogen but is generally not mutagenic. The evidence that arsenic induces both loss of global DNA methylation and gene promoter DNA hypermethylation have suggested that epigenetic mechanisms may play an important role in arsenic induced carcinogenesis. In the present study, we examined the change in histone methylation by arsenic exposure. In human lung carcinoma A549 cells, exposure to inorganic trivalent arsenic (arsenite) increased H3K9 di-methylation (H3K9me2) and decreased H3K27 tri-methylation (H3K27me3), both of which represent gene silencing marks, while increasing the global levels of the H3K4 tri-methylation (H3K4me3), a gene activating mark. The increase in H3K9me2 was mediated by an increase in the histone methyltransferase G9a protein and mRNA levels. We also observed strikingly significant altered histone modifications induced by very low dose (0.1 µM) arsenite. Taken together, these results suggest a potential mechanism by which arsenic induces carcinogenesis through the alteration of specific histone methylations that represent both gene silencing and activating marks. Furthermore, these marks are known to affect DNA methylation, and it is likely that arsenic's effect is not limited to histone modifications alone, but extends, perhaps by them, to DNA methylations as well. Future studies in our laboratory will address the genomic location of these silencing and activating marks using ChIP-on-chip technology.

Key Words: Arsenite • histone • methylation • epigenetic • H3K4 • H3K9 • H3K27 • G9a • JHDM2A

{dagger} These authors contributed equally.

Received November 14, 2007; revised January 31, 2008; accepted February 23, 2008.


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