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Carcinogenesis Advance Access originally published online on August 1, 2008
Carcinogenesis 2008 29(11):2175-2181; doi:10.1093/carcin/bgn179
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Selenite reactivates silenced genes by modifying DNA methylation and histones in prostate cancer cells

Nong Xiang1, Rui Zhao1, Guoqing Song1 and Weixiong Zhong1,2,*

1 Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
2 Department of Pathology and Laboratory Medicine Service, William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA

* To whom correspondence should be addressed. Tel: +1 608 265 6069; Fax: +1 608 265 6215; Email: wzhong3{at}wisc.edu

DNA hypermethylation is a common epigenetic alteration in human prostate cancer and is considered to contribute to development of this disease. Accumulating data suggest that dietary factors may alter cancer risk by modifications of epigenetic processes in the cell. The present study was designed to investigate whether selenium (Se) would alter epigenetic events to regulate methylation-silenced genes in human prostate cancer cells. DNA methylation, histone modifications and gene expression were studied in LNCaP cells after selenite treatment using polymerase chain reaction, western blot analysis, chromatin immunoprecipitation assay and enzymatic activity assay. Our study shows that selenite treatment caused partial promoter DNA demethylation and reexpression of the {pi}-class glutathione-S-transferase (GSTP1) in LNCaP cells in a dose- and time-dependent manner. Selenite treatment decreased messenger RNA levels of DNA methyltransferases (DNMTs) 1 and 3A and protein levels of DNMT1. Selenite also decreased histone deacetylase activity and increased levels of acetylated lysine 9 on histone H3 (H3-Lys 9), but decreased levels of methylated H3-Lys 9. Selenite treatment reduced levels of DNMT1 and methylated H3-Lys 9 associated with the GSTP1 promoter, but increased levels of acetylated H3-Lys 9 associated with this promoter. Additionally, selenite treatment decreased general DNA methylation and caused partial promoter demethylation and reexpression of the tumor suppressor adenomatous polyposis coli and cellular stress response 1, a gene involving tumor growth and metastasis. Our study demonstrates that Se can epigenetically modulate DNA and histones to activate methylation-silenced genes. These epigenetic modifications may contribute to cancer prevention by Se.

Abbreviations: APC, adenomatous polyposis coli; 5-Aza-dC, 5-aza-2'-deoxycytidine; CSR1, cellular stress response 1; DNMT, DNA methyltransferase; GSTP1, {pi}-class glutathione-S-transferase; HDAC, histone deacetylase; H3-Lys 9, lysine 9 on histone H3; mRNA, messenger RNA; MS-PCR, methylation-specific polymerase chain reaction; PCR, polymerase chain reaction; RT–PCR, reverse transcripton–polymerase chain reaction; Se, selenium; TSA, trichostatin A

Received March 8, 2008; revised July 28, 2008; accepted July 29, 2008.


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