EZH2-mediated concordant repression of Wnt antagonists promotes β-catenin-dependent hepatocarcinogenesis

Alfred S L Cheng, Suki S. Lau, Yangchao Chen, Yutaka Kondo, May S. Li, Hai Feng, Arthur K. Ching, Kin F. Cheung, Hoi K. Wong, Joanna H. Tong, Hongchuan Jin, Kwong W. Choy, Jun Yu, Ka F. To, Nathalie Wong, Hui-ming Huang, Joseph J Y Sung

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

Original languageEnglish
Pages (from-to)4028-4039
Number of pages12
JournalCancer Research
Volume71
Issue number11
DOIs
StatePublished - Jun 1 2011
Externally publishedYes

Fingerprint

Catenins
Polycomb Repressive Complex 2
Hepatocellular Carcinoma
Histone Code
Histone Deacetylase 1
Enhancer of Zeste Homolog 2 Protein
TCF Transcription Factors
Neoplasms
Wnt Signaling Pathway
Chromatin Immunoprecipitation
Growth
Epigenomics
Histones
Lysine
Hepatocytes
Catalytic Domain
Carcinogenesis
Up-Regulation
Down-Regulation
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cheng, A. S. L., Lau, S. S., Chen, Y., Kondo, Y., Li, M. S., Feng, H., ... Sung, J. J. Y. (2011). EZH2-mediated concordant repression of Wnt antagonists promotes β-catenin-dependent hepatocarcinogenesis. Cancer Research, 71(11), 4028-4039. https://doi.org/10.1158/0008-5472.CAN-10-3342

EZH2-mediated concordant repression of Wnt antagonists promotes β-catenin-dependent hepatocarcinogenesis. / Cheng, Alfred S L; Lau, Suki S.; Chen, Yangchao; Kondo, Yutaka; Li, May S.; Feng, Hai; Ching, Arthur K.; Cheung, Kin F.; Wong, Hoi K.; Tong, Joanna H.; Jin, Hongchuan; Choy, Kwong W.; Yu, Jun; To, Ka F.; Wong, Nathalie; Huang, Hui-ming; Sung, Joseph J Y.

In: Cancer Research, Vol. 71, No. 11, 01.06.2011, p. 4028-4039.

Research output: Contribution to journalArticle

Cheng, ASL, Lau, SS, Chen, Y, Kondo, Y, Li, MS, Feng, H, Ching, AK, Cheung, KF, Wong, HK, Tong, JH, Jin, H, Choy, KW, Yu, J, To, KF, Wong, N, Huang, H & Sung, JJY 2011, 'EZH2-mediated concordant repression of Wnt antagonists promotes β-catenin-dependent hepatocarcinogenesis', Cancer Research, vol. 71, no. 11, pp. 4028-4039. https://doi.org/10.1158/0008-5472.CAN-10-3342
Cheng, Alfred S L ; Lau, Suki S. ; Chen, Yangchao ; Kondo, Yutaka ; Li, May S. ; Feng, Hai ; Ching, Arthur K. ; Cheung, Kin F. ; Wong, Hoi K. ; Tong, Joanna H. ; Jin, Hongchuan ; Choy, Kwong W. ; Yu, Jun ; To, Ka F. ; Wong, Nathalie ; Huang, Hui-ming ; Sung, Joseph J Y. / EZH2-mediated concordant repression of Wnt antagonists promotes β-catenin-dependent hepatocarcinogenesis. In: Cancer Research. 2011 ; Vol. 71, No. 11. pp. 4028-4039.
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abstract = "Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb-repressive complex 2 (PRC2) that represses gene transcription through histone H3 lysine 27 trimethylation (H3K27me3). Although EZH2 is abundantly present in various cancers, the molecular consequences leading to oncogenesis remain unclear. Here, we show that EZH2 concordantly silences the Wnt pathway antagonists operating at several subcellular compartments, which in turn activate Wnt/β-catenin signaling in hepatocellular carcinomas (HCC). Chromatin immunoprecipitation promoter array and gene expression analyses in HCCs revealed EZH2 occupancy and reduced expression of Wnt antagonists, including the growth-suppressive AXIN2, NKD1, PPP2R2B, PRICKLE1, and SFRP5. Knockdown of EZH2 reduced the promoter occupancy of PRC2, histone deacetylase 1 (HDAC1), and H3K27me3, whereas the activating histone marks were increased, leading to the transcriptional upregulation of the Wnt antagonists. Combinatorial EZH2 and HDAC inhibition dramatically reduced the levels of nuclear β-catenin, T-cell factor-dependent transcriptional activity, and downstream pro-proliferative targets CCND1 and EGFR. Functional analysis revealed that downregulation of EZH2 reduced HCC cell growth, partially through the inhibition of β-catenin signaling. Conversely, ectopic overexpression of EZH2 in immortalized hepatocytes activated Wnt/β-catenin signaling to promote cellular proliferation. In human HCCs, concomitant overexpression of EZH2 and β-catenin was observed in one-third (61/179) of cases and significantly correlated with tumor progression. Our data indicate that EZH2-mediated epigenetic silencing contributes to constitutive activation of Wnt/β-catenin signaling and consequential proliferation of HCC cells, thus representing a novel therapeutic target for this highly malignant tumor.",
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AU - Cheng, Alfred S L

AU - Lau, Suki S.

AU - Chen, Yangchao

AU - Kondo, Yutaka

AU - Li, May S.

AU - Feng, Hai

AU - Ching, Arthur K.

AU - Cheung, Kin F.

AU - Wong, Hoi K.

AU - Tong, Joanna H.

AU - Jin, Hongchuan

AU - Choy, Kwong W.

AU - Yu, Jun

AU - To, Ka F.

AU - Wong, Nathalie

AU - Huang, Hui-ming

AU - Sung, Joseph J Y

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AB - Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb-repressive complex 2 (PRC2) that represses gene transcription through histone H3 lysine 27 trimethylation (H3K27me3). Although EZH2 is abundantly present in various cancers, the molecular consequences leading to oncogenesis remain unclear. Here, we show that EZH2 concordantly silences the Wnt pathway antagonists operating at several subcellular compartments, which in turn activate Wnt/β-catenin signaling in hepatocellular carcinomas (HCC). Chromatin immunoprecipitation promoter array and gene expression analyses in HCCs revealed EZH2 occupancy and reduced expression of Wnt antagonists, including the growth-suppressive AXIN2, NKD1, PPP2R2B, PRICKLE1, and SFRP5. Knockdown of EZH2 reduced the promoter occupancy of PRC2, histone deacetylase 1 (HDAC1), and H3K27me3, whereas the activating histone marks were increased, leading to the transcriptional upregulation of the Wnt antagonists. Combinatorial EZH2 and HDAC inhibition dramatically reduced the levels of nuclear β-catenin, T-cell factor-dependent transcriptional activity, and downstream pro-proliferative targets CCND1 and EGFR. Functional analysis revealed that downregulation of EZH2 reduced HCC cell growth, partially through the inhibition of β-catenin signaling. Conversely, ectopic overexpression of EZH2 in immortalized hepatocytes activated Wnt/β-catenin signaling to promote cellular proliferation. In human HCCs, concomitant overexpression of EZH2 and β-catenin was observed in one-third (61/179) of cases and significantly correlated with tumor progression. Our data indicate that EZH2-mediated epigenetic silencing contributes to constitutive activation of Wnt/β-catenin signaling and consequential proliferation of HCC cells, thus representing a novel therapeutic target for this highly malignant tumor.

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