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

• Published in: The Journal of biological chemistry 2008-11, Vol.283 (45), p.30919-30932
• Main Authors: Ko, Chiung-Yuan, Hsu, Hey-Chi, Shen, Meng-Ru, Chang, Wen-Chang, Wang, Ju-Ming
• Format: Article
• Language: English
• Subjects: Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; CCAAT-Enhancer-Binding Protein-beta - biosynthesis; CCAAT-Enhancer-Binding Protein-beta - genetics; DNA Modification Methylases - genetics; DNA Modification Methylases - metabolism; Female; Gene Expression Regulation, Neoplastic - genetics; Gene Silencing; HeLa Cells; Humans; Male; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Polycomb Repressive Complex 2; Promoter Regions, Genetic - genetics; Transcription, Chromatin, and Epigenetics; Tumor Suppressor Proteins - biosynthesis; Tumor Suppressor Proteins - genetics; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism; YY1 Transcription Factor - genetics; YY1 Transcription Factor - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M804029200

Human CCAAT/enhancer-binding protein δ (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.