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J. Biol. Chem., Vol. 283, Issue 45, 30919-30932, November 7, 2008

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Epigenetic Silencing of CCAAT/Enhancer-binding Protein Activity by YY1/Polycomb Group/DNA Methyltransferase Complex^*

Chiung-Yuan Ko, Hey-Chi Hsu, Meng-Ru Shen^¶, Wen-Chang Chang^¶||**1, and Ju-Ming Wang^||**2

From the Institute of Basic Medical Sciences and ^¶Department of Pharmacology, College of Medicine, ^||Institute of Biosignal Transduction and ^**Institute of Bioinformation, College of Bioscience and Biotechnology, and Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan 70101 and the Department of Pathology, College of Medicine, National Taiwan University, Taipei 10002, Taiwan

Human CCAAT/enhancer-binding protein (CEBPD) has been reported as a tumor suppressor because it both induces growth arrest involved in differentiation and plays a crucial role as a regulator of pro-apoptotic gene expression. In this study, CEBPD gene expression is down-regulated, and "loss of function" alterations in CEBPD gene expression are observed in cervical cancer and hepatocellular carcinoma. Suppressor of zeste 12 (SUZ12), a component of the polycomb repressive complex 2 (PRC2), silences CEBPD promoter activity, enhancing the methylation of exogenous CEBPD promoter through the proximal CpG islands. Moreover, this molecular approach is consistent with the opposite mRNA expression pattern between SUZ12 and CEBPD in cervical cancer and hepatocellular carcinoma patients. We further demonstrated that Yin-Yang-1 (YY1) physically interacts with SUZ12 and can act as a mediator to recruit the polycomb group proteins and DNA methyltransferases to participate in the CEBPD gene silencing process. Taking these results into consideration, we not only demonstrate the advantage of SUZ12-silenced CEBPD expression in tumor formation but also clarify an in vivo evidence for YY1-mediated silencing paths of SUZ12 and DNA methyltransferases on the CEBPD promoter.

Received for publication, May 27, 2008 , and in revised form, August 26, 2008.

^* This work was supported by and the funding to pay the Open Access publication charges for this article were provided by Grant 96-2320-B-006-044-MY2 from the Taiwan National Science Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: No. 1 University Rd., Dept. of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Tel.: 886-6-2353535 (Ext. 5496); Fax: 886-6-2749296; E-mail: wcchang{at}mail.ncku.edu.tw. ² To whom correspondence may be addressed: No. 1 University Rd., Institute of Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan. Tel.: 886-6-2757575 (Ext. 31067); Fax: 886-6-2083663; E-mail: wwwjm4721{at}yahoo.com.tw.

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