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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.
PMID
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Authors

Mayor MeshTerms

Gene Silencing

Keywords

ChIP-seq

DNA methylation

EZH2

histone modification

liver cancer

Journal Title the journal of pathology
Publication Year Start




PMID- 26800240
OWN - NLM
STAT- MEDLINE
DCOM- 20160801
LR  - 20161126
IS  - 1096-9896 (Electronic)
IS  - 0022-3417 (Linking)
VI  - 238
IP  - 5
DP  - 2016 Apr
TI  - Yin Yang 1-mediated epigenetic silencing of tumour-suppressive microRNAs
      activates nuclear factor-kappaB in hepatocellular carcinoma.
PG  - 651-64
LID - 10.1002/path.4688 [doi]
AB  - 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-kappaB (NF-kappaB). Functionally, YY1 
      promoted HCC tumourigenicity and inhibited apoptosis of HCC cells, at least
      partially through NF-kappaB activation. In conclusion, YY1 overexpression
      contributes to EZH2 recruitment for H3K27me3-mediated silencing of
      tumour-suppressive microRNAs, thereby activating NF-kappaB signalling in
      hepatocarcinogenesis.
CI  - Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published
      by John Wiley & Sons, Ltd.
FAU - Tsang, Daisy P F
AU  - Tsang DP
AD  - Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The
      Chinese University of Hong Kong, Hong Kong SAR, China.
AD  - Department of Medicine and Therapeutics, The Chinese University of Hong Kong,
      Hong Kong SAR, China.
FAU - Wu, William K K
AU  - Wu WK
AD  - Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The
      Chinese University of Hong Kong, Hong Kong SAR, China.
AD  - Department of Anaesthesia and Intensive Care, The Chinese University of Hong
      Kong, Hong Kong SAR, China.
FAU - Kang, Wei
AU  - Kang W
AD  - Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
      SAR, China.
FAU - Lee, Ying-Ying
AU  - Lee YY
AD  - Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The
      Chinese University of Hong Kong, Hong Kong SAR, China.
AD  - Department of Medicine and Therapeutics, The Chinese University of Hong Kong,
      Hong Kong SAR, China.
FAU - Wu, Feng
AU  - Wu F
AD  - Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
      SAR, China.
FAU - Yu, Zhuo
AU  - Yu Z
AD  - Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The
      Chinese University of Hong Kong, Hong Kong SAR, China.
FAU - Xiong, Lei
AU  - Xiong L
AD  - Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
      SAR, China.
FAU - Chan, Anthony W
AU  - Chan AW
AD  - Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
      SAR, China.
FAU - Tong, Joanna H
AU  - Tong JH
AD  - Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
      SAR, China.
FAU - Yang, Weiqin
AU  - Yang W
AD  - Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The
      Chinese University of Hong Kong, Hong Kong SAR, China.
AD  - Department of Medicine and Therapeutics, The Chinese University of Hong Kong,
      Hong Kong SAR, China.
FAU - Li, May S M
AU  - Li MS
AD  - Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The
      Chinese University of Hong Kong, Hong Kong SAR, China.
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong
      SAR, China.
FAU - Lau, Suki S
AU  - Lau SS
AD  - Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The
      Chinese University of Hong Kong, Hong Kong SAR, China.
FAU - Li, Xiangchun
AU  - Li X
AD  - Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The
      Chinese University of Hong Kong, Hong Kong SAR, China.
AD  - Department of Medicine and Therapeutics, The Chinese University of Hong Kong,
      Hong Kong SAR, China.
FAU - Lee, Sau-Dan
AU  - Lee SD
AD  - Department of Computer Science and Engineering, The Chinese University of Hong
      Kong, Hong Kong SAR, China.
FAU - Yang, Yihua
AU  - Yang Y
AD  - Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong,
      Hong Kong SAR, China.
FAU - Lai, Paul B S
AU  - Lai PB
AD  - Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The
      Chinese University of Hong Kong, Hong Kong SAR, China.
AD  - Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China.
FAU - Yu, Dae-Yeul
AU  - Yu DY
AD  - Disease Model Research Laboratory, Aging Research Center and World Class
      Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon,
      Republic of Korea.
FAU - Xu, Gang
AU  - Xu G
AD  - Department of Medicine and Therapeutics, The Chinese University of Hong Kong,
      Hong Kong SAR, China.
FAU - Lo, Kwok-Wai
AU  - Lo KW
AD  - Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
      SAR, China.
FAU - Chan, Matthew T V
AU  - Chan MT
AD  - Department of Anaesthesia and Intensive Care, The Chinese University of Hong
      Kong, Hong Kong SAR, China.
FAU - Wang, Huating
AU  - Wang H
AD  - Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong,
      Hong Kong SAR, China.
FAU - Lee, Tin L
AU  - Lee TL
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong
      SAR, China.
FAU - Yu, Jun
AU  - Yu J
AD  - Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The
      Chinese University of Hong Kong, Hong Kong SAR, China.
AD  - Department of Medicine and Therapeutics, The Chinese University of Hong Kong,
      Hong Kong SAR, China.
FAU - Wong, Nathalie
AU  - Wong N
AD  - Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The
      Chinese University of Hong Kong, Hong Kong SAR, China.
AD  - Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
      SAR, China.
FAU - Yip, Kevin Y
AU  - Yip KY
AD  - Department of Computer Science and Engineering, The Chinese University of Hong
      Kong, Hong Kong SAR, China.
FAU - To, Ka-Fai
AU  - To KF
AD  - Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The
      Chinese University of Hong Kong, Hong Kong SAR, China.
AD  - Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
      SAR, China.
FAU - Cheng, Alfred S L
AU  - Cheng AS
AD  - Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The
      Chinese University of Hong Kong, Hong Kong SAR, China.
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong
      SAR, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Pathol
JT  - The Journal of pathology
JID - 0204634
RN  - 0 (Histones)
RN  - 0 (MicroRNAs)
RN  - 0 (NF-kappa B)
RN  - 0 (Trans-Activators)
RN  - 0 (YY1 Transcription Factor)
RN  - 0 (YY1 protein, human)
RN  - 0 (hepatitis B virus X protein)
RN  - EC 2.1.1.43 (EZH2 protein, human)
RN  - EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein)
RN  - EC 2.1.1.43 (Polycomb Repressive Complex 2)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Binding Sites
MH  - Carcinoma, Hepatocellular/genetics/*metabolism/pathology/virology
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - DNA Methylation
MH  - Enhancer of Zeste Homolog 2 Protein
MH  - Gene Expression Regulation, Neoplastic
MH  - *Gene Silencing
MH  - Histones/metabolism
MH  - Humans
MH  - Liver Neoplasms/genetics/*metabolism/pathology/virology
MH  - Lysine
MH  - Methylation
MH  - Mice, Nude
MH  - Mice, Transgenic
MH  - MicroRNAs/genetics/*metabolism
MH  - NF-kappa B/*metabolism
MH  - Polycomb Repressive Complex 2/genetics/metabolism
MH  - Promoter Regions, Genetic
MH  - RNA Interference
MH  - Signal Transduction
MH  - Time Factors
MH  - Trans-Activators/genetics/metabolism
MH  - Transfection
MH  - Tumor Burden
MH  - Up-Regulation
MH  - YY1 Transcription Factor/genetics/*metabolism
OTO - NOTNLM
OT  - ChIP-seq
OT  - DNA methylation
OT  - EZH2
OT  - histone modification
OT  - liver cancer
EDAT- 2016/01/23 06:00
MHDA- 2016/08/02 06:00
CRDT- 2016/01/23 06:00
PHST- 2015/10/22 00:00 [received]
PHST- 2015/12/19 00:00 [revised]
PHST- 2016/01/05 00:00 [accepted]
PHST- 2016/01/23 06:00 [entrez]
PHST- 2016/01/23 06:00 [pubmed]
PHST- 2016/08/02 06:00 [medline]
AID - 10.1002/path.4688 [doi]
PST - ppublish
SO  - J Pathol. 2016 Apr;238(5):651-64. doi: 10.1002/path.4688.