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Carcinogenesis Advance Access originally published online on March 4, 2008
Carcinogenesis 2008 29(9):1831-1836; 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*

Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA

* To whom correspondence should be addressed. Tel: +1 845 731 3515; Fax: +1 845 351 2118; Email: max.costa{at}nyumc.org

Arsenic (As) is a well-characterized human carcinogen but is generally not mutagenic. The evidence that As induces both loss of global DNA methylation and gene promoter DNA hypermethylation has suggested that epigenetic mechanisms may play an important role in As-induced carcinogenesis. In the present study, we examined the change in histone methylation by As exposure. In human lung carcinoma A549 cells, exposure to inorganic trivalent As (arsenite) increased H3K9 dimethylation (H3K9me2) and decreased H3K27 trimethylation (H3K27me3), both of which represent gene silencing marks, while increasing the global levels of the H3K4 trimethylation (H3K4me3), a gene-activating mark. The increase in H3K9me2 was mediated by an increase in the histone methyltransferase G9a protein and messenger RNA 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 As 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.

Abbreviations: As, arsenic; mRNA, messenger RNA

{dagger} These authors contributed equally to this work.

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


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