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J Pathol. 2016 Apr;238(5):651-64. doi: 10.1002/path.4688.

Yin Yang 1-mediated epigenetic silencing of tumour-suppressive microRNAs activates nuclear factor-κB in hepatocellular carcinoma.

Author information

1
Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.
2
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
3
Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR, China.
4
Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
5
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
6
Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China.
7
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong SAR, China.
8
Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China.
9
Disease Model Research Laboratory, Aging Research Center and World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.

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.

KEYWORDS:

ChIP-seq; DNA methylation; EZH2; histone modification; liver cancer

PMID:
26800240
DOI:
10.1002/path.4688
[Indexed for MEDLINE]

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