Yin Yang 1-mediated epigenetic silencing of tumour-suppressive microRNAs activates nuclear factor-κB in hepatocellular carcinoma
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摘要Enhancer of zeste homolog 2 (EZH2) catalyses histone H3 lysine 27 trimethylation (H3K27me3) to silence tumour-suppressor genes in hepatocellular carcinoma (HCC) but the process of locus-specific recruitment remains elusive. Here we investigated the transcription factors involved and the molecular consequences in HCC development. The genome-wide distribution of H3K27me3 was determined by chromatin immunoprecipitation coupled with high-throughput sequencing or promoter array analyses in HCC cells from hepatitis B virus (HBV) X protein transgenic mouse and human cell models. Transcription factor binding site analysis was performed to identify EZH2-interacting transcription factors followed by functional characterization. Our cross-species integrative analysis revealed a crucial link between Yin Yang 1 (YY1) and EZH2-mediated H3K27me3 in HCC. Gene expression analysis of human HBV-associated HCC specimens demonstrated concordant overexpression of YY1 and EZH2, which correlated with poor survival of patients in advanced stages. The YY1 binding motif was significantly enriched in both in vivo and in vitro H3K27me3-occupied genes, including genes for 15 tumour-suppressive microRNAs. Knockdown of YY1 reduced not only global H3K27me3 levels, but also EZH2 and H3K27me3 promoter occupancy and DNA methylation, leading to the transcriptional up-regulation of microRNA-9 isoforms in HCC cells. Concurrent EZH2 knockdown and 5-aza-2'-deoxycytidine treatment synergistically increased the levels of microRNA-9, which reduced the expression and transcriptional activity of nuclear factor-B (NF-B). Functionally, YY1 promoted HCC tumourigenicity and inhibited apoptosis of HCC cells, at least partially through NF-B activation. In conclusion, YY1 overexpression contributes to EZH2 recruitment for H3K27me3-mediated silencing of tumour-suppressive microRNAs, thereby activating NF-B signalling in hepatocarcinogenesis. Copyright (c) 2016 Pathological Society of Great Britain and Ireland.
出版社接受日期16.03.2016
著者Tsang DPF, Wu WKK, Kang W, Lee YY, Wu F, Yu Z, Xiong L, Chan AW, Tong JH, Yang WQ, Li MSM, Lau SS, Li XC, Lee SD, Yang YH, Lai PBS, Yu DY, Xu G, Lo KW, Chan MTV, Wang HT, Lee TL, Yu J, Wong N, Yip KY, To KF, Cheng ASL, Cheng ASL
期刊名稱Journal of Pathology
出版年份2016
月份4
卷號238
期次5
出版社WILEY-BLACKWELL
頁次651 - 664
國際標準期刊號0022-3417
電子國際標準期刊號1096-9896
語言英式英語
關鍵詞EZH2, histone modification, DNA methylation, liver cancer, ChIP-seq
Web of Science 學科類別Oncology;Pathology;Oncology;Pathology

上次更新時間 2020-24-11 於 01:19