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Molecular and Cellular Biology, May 2008, p. 3219-3235, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.01516-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Histone Deacetylase Inhibitor Depsipeptide Activates Silenced Genes through Decreasing both CpG and H3K9 Methylation on the Promoter{triangledown}

Li-Peng Wu,1,2,{dagger} Xi Wang,1,{dagger} Lian Li,1 Ying Zhao,1,2 Shaoli Lu,1 Yu Yu,1 Wen Zhou,1 Xiangyu Liu,1 Jing Yang,1 Zhixin Zheng,1 Hui Zhang,1,3 Jingnan Feng,1 Yang Yang,1 Haiying Wang,1 and Wei-Guo Zhu1,2*

Department of Biochemistry and Molecular Biology,1 School of Oncology,2 Department of Surgery, The Secondary Affiliated Hospital, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100083, China3

Received 21 August 2007/ Returned for modification 17 October 2007/ Accepted 3 March 2008

Histone deacetylase inhibitor (HDACi) has been shown to demethylate the mammalian genome, which further strengthens the concept that DNA methylation and histone modifications interact in regulation of gene expression. Here, we report that an HDAC inhibitor, depsipeptide, exhibited significant demethylating activity on the promoters of several genes, including p16, SALL3, and GATA4 in human lung cancer cell lines H719 and H23, colon cancer cell line HT-29, and pancreatic cancer cell line PANC1. Although expression of DNA methyltransferase 1 (DNMT1) was not affected by depsipeptide, a decrease in binding of DNMT1 to the promoter of these genes played a dominant role in depsipeptide-induced demethylation and reactivation. Depsipeptide also suppressed expression of histone methyltransferases G9A and SUV39H1, which in turn resulted in a decrease of di- and trimethylated H3K9 around these genes' promoter. Furthermore, both loading of heterochromatin-associated protein 1 (HP1{alpha} and HP1β) to methylated H3K9 and binding of DNMT1 to these genes' promoter were significantly reduced in depsipeptide-treated cells. Similar DNA demethylation was induced by another HDAC inhibitor, apicidin, but not by trichostatin A. Our data describe a novel mechanism of HDACi-mediated DNA demethylation via suppression of histone methyltransferases and reduced recruitment of HP1 and DNMT1 to the genes' promoter.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100083, China. Phone: 86-10-82802235. Fax: 86-10-82805079. E-mail: zhuweiguo{at}bjmu.edu.cn

{triangledown} Published ahead of print on 10 March 2008.

{dagger} L.-P.W. and X.W. contributed equally to this work.

Molecular and Cellular Biology, May 2008, p. 3219-3235, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.01516-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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