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

Abstract

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.

HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

“…2B). These results were consistent with those obtained in our previous study suggesting that the Cebpd promoter is hypermethylated in liver cancer (16). Next, we assessed the expression and role of CEBPD in a HFD/DEN-induced mouse liver cancer model (21).…”

“…Luciferase activity was measured in the lysates of the transfectants as described before (16 Apoptotic cell death analysis using flow cytometry Typical cell-cycle histograms were analyzed using flow cytometry after exposure with or without 10 mmol/L 5-AzadC for 48 hours and followed by treatment with 100 mmol/L HMDB. Apoptotic cell death of experimental cells was harvested and fixed in 75% ethanol at À20 C for 24 hours.…”

“…A recent study demonstrated that loss of CEBPD might contribute to the initiation of breast cancer (15). Moreover, inactivated CEBPD was observed in HCC and cervical cancer via an epigenetic effect (16). Transcription factor Yin-Yang 1 (YY1) physically interacts with SUZ12 and can act as a mediator to recruit PcG proteins and DNA methyltransferases to participate in CEBPD gene desensitization in cancer cells (16).…”

“…Moreover, inactivated CEBPD was observed in HCC and cervical cancer via an epigenetic effect (16). Transcription factor Yin-Yang 1 (YY1) physically interacts with SUZ12 and can act as a mediator to recruit PcG proteins and DNA methyltransferases to participate in CEBPD gene desensitization in cancer cells (16). However, details of the molecular mechanism and clinical relevance of CEBPD inactivation in HCC remain unknown.…”

C/EBPδ targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression

“…T he transcription factor CCAAT/enhancer binding protein δ (C/EBPδ, CEBPD, NFIL-6β) is down-regulated in several types of tumors, including cervix, liver, and breast (1)(2)(3)(4)(5). In vitro, C/EBPδ inhibits the growth of tumor cell lines, is associated with G 0 growth arrest, or induces differentiation (6)(7)(8), and promotes genomic stability of mouse embryo fibroblasts (MEFs) (9).…”