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

Daisy P.F. Tsang, William K.K. Wu, Wei Kang, Ying Ying Lee, Feng Wu, Zhuo Yu, Lei Xiong, Anthony W. Chan, Joanna H. Tong, Weiqin Yang, May S.M. Li, Suki S. Lau, Xiangchun Li, Sau Dan Lee, Yihua Yang, Paul B.S. Lai, Dae Yeul Yu, Gang XU, Kwok Wai Lo, Matthew T.V. ChanHuating Wang, Tin L. Lee, Jun Yu, Nathalie Wong, Kevin Y. Yip, Ka Fai To, Alfred S.L. Cheng*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)651-664
Number of pages14
JournalJournal of Pathology
Volume238
Issue number5
DOIs
Publication statusPublished - 1 Apr 2016

Scopus Subject Areas

  • Pathology and Forensic Medicine

User-Defined Keywords

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

Fingerprint

Dive into the research topics of 'Yin Yang 1-mediated epigenetic silencing of tumour-suppressive microRNAs activates nuclear factor-κB in hepatocellular carcinoma'. Together they form a unique fingerprint.

Cite this