Transcriptional silencing of the TMS1/ASC tumour suppressor gene by an epigenetic mechanism in hepatocellular carcinoma cells

Authors

  • C Zhang,

    1. Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, People's Republic of China
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    • These authors contributed equally to this work.

  • H Li,

    1. Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, People's Republic of China
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    • These authors contributed equally to this work.

  • G Zhou,

    Corresponding author
    1. Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, People's Republic of China
    • Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, China.
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  • Q Zhang,

    1. Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, People's Republic of China
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  • T Zhang,

    1. Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, People's Republic of China
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  • J Li,

    1. Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, People's Republic of China
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  • J Zhang,

    1. Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, People's Republic of China
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  • J Hou,

    1. Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, People's Republic of China
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  • CT Liew,

    1. Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, People's Republic of China
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  • D Yin

    1. Department of Internal Medicine, Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
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  • No conflicts of interest were declared.

Abstract

DNA methylation and histone modifications have emerged as key mechanisms in transcriptional regulation. The target of methylation-induced silencing 1 (TMS1) is a bipartite protein. Recent studies have indicated that methylation-associated silencing of TMS1 occurs in many cancers. However, whether and how TMS1 is regulated by epigenetic mechanisms in cancers remains unknown. In this study we showed that methylation of the TMS1 promoter occurred in five of six hepatocellular carcinoma (HCC) cell lines. TMS1 expression was reduced in four HCC cell lines and correlated with methylation status. Furthermore, the TMS1 promoter was completely methylated and mRNA expression was undetectable. TMS1 expression could be restored by 5-aza-2′-deoxycitidine (5-Aza-dC) (a DNA methyltransferase inhibitor) or trichostatin A (TSA) (a histone deacetylase inhibitor) alone and the promoter methylation was partially reversible. TSA was more efficient than 5-Aza-dC in inducing TMS1 expression, and the combination of 5-Aza-dC and TSA resulted in markedly synergistic reactivation of the gene and completely reversed promoter methylation. Interestingly, TMS1 promoter methylation-associated gene silencing was accompanied by histone H3 Lysine 9 (H3K9) hypoacetylation and trimethylation. 5-Aza-dC and/or TSA also had some effect on conversion of methylated to acetylated H3K9 in restoring TMS1. This conversion was dynamic at the TMS1 promoter and a decrease in H3K9 trimethylation preceded an increase in H3K9 acetylation after 5-Aza-dC and/or TSA treatment. Our results thus suggest that epigenetic inactivation of TMS1 expression is regulated by promoter hypermethylation and H3K9 modifications in a coordinated way. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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