Human Molecular Genetics, 2003, Vol. 12, No. 15 1791-1800
DOI: 10.1093/hmg/ddg204
© 2003 Oxford University Press
Reactivation of the silenced and imprinted alleles of ARHI is associated with increased histone H3 acetylation and decreased histone H3 lysine 9 methylation
1Department of Experimental Therapeutics, 2Department of Biochemistry and Molecular Biology, and 3Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA and 4Division of Molecular and Cell Genetics, Department of Molecular and Cellular Biology, School of Life Sciences, Faculty of Medicine, Tottori University, Nishimachi 86, Yonago, Tottori 683-8503, Japan
Received May 10, 2003; Accepted June 4, 2003
ARHI has been identified as a maternally imprinted tumor suppressor gene that maps to chromosome 1p31 and whose expression is markedly down-regulated in breast cancer. To explore possible mechanisms that could silence ARHI expression, we have tested the importance of DNA methylation, histone acetylation and histone methylation in regulating ARHI expression. We found that treatment with CpG demethylating agents and/or histone deacetylase inhibitors could reactivate both the silenced and the imprinted alleles of this tumor suppressor gene. Reactivation of ARHI expression by these reagents is related to the methylation status of the CpG islands in the ARHI promoter, especially CpG island II. Chromatin immunoprecipitation assays revealed that histone H3 lysine 9/18 acetylation levels associated with ARHI in normal cells were significantly higher than those in breast cancer cell lines that lacked ARHI expression. Treatment with a CpG demethylating agent and/or histone deacetylase inhibitor could increase ARHI expression in breast cancer cells, with a corresponding increase in histone H3 lysine 9/18 acetylation and decrease in histone H3 lysine 9 methylation.
* To whom correspondence should be addressed at: Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Box 354, 1515 Holcombe Blvd, Houston, TX 77030, USA. Tel: +1 7137923790; Fax: +1 7137452107; Email: yyu{at}mdanderson.org
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