title: Yin Yang 1-mediated epigenetic silencing of tumour-suppressive microRNAs activates nuclear factor-κB in hepatocellular carcinoma.
abstract: 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-κB (NF-κB). Functionally, YY1 promoted HCC tumourigenicity and inhibited apoptosis of HCC cells, at least partially through NF-κB activation. In conclusion, YY1 overexpression contributes to EZH2 recruitment for H3K27me3-mediated silencing of tumour-suppressive microRNAs, thereby activating NF-κB signalling in hepatocarcinogenesis.
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Daisy P F
authors.initials: DP
authors.lastname: Tsang
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.|Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: William K K
authors.initials: WK
authors.lastname: Wu
authors.affiliation: Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Kang
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Lee
authors.affiliation: Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wu
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xiong
authors.affiliation: Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Chan
authors.affiliation: Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Joanna H
authors.initials: JH
authors.lastname: Tong
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Weiqin
authors.initials: W
authors.lastname: Yang
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.|School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: May S M
authors.initials: MS
authors.lastname: Li
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Suki S
authors.initials: SS
authors.lastname: Lau
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Xiangchun
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Sau-Dan
authors.initials: SD
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.|Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Paul B S
authors.initials: PB
authors.lastname: Lai
authors.affiliation: Disease Model Research Laboratory, Aging Research Center and World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Dae-Yeul
authors.initials: DY
authors.lastname: Yu
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Kwok-Wai
authors.initials: KW
authors.lastname: Lo
authors.affiliation: Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Matthew T V
authors.initials: MT
authors.lastname: Chan
authors.affiliation: Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Huating
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Tin L
authors.initials: TL
authors.lastname: Lee
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.|Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wong
authors.affiliation: Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Kevin Y
authors.initials: KY
authors.lastname: Yip
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.|Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.|School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Alfred S L
authors.initials: AS
authors.lastname: Cheng
mesh_terms: D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008239:Lysine; D008745:Methylation; D008819:Mice, Nude; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; D035683:MicroRNAs; D016328:NF-kappa B; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; C057628:hepatitis B virus X protein; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine
keywords: ChIP-seq; DNA methylation; EZH2; histone modification; liver cancer