These authors contributed equally to this work.
Transcriptional silencing of the TMS1/ASC tumour suppressor gene by an epigenetic mechanism in hepatocellular carcinoma cells†
Article first published online: 30 APR 2007
Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 212, Issue 2, pages 134–142, June 2007
How to Cite
Zhang, C., Li, H., Zhou, G., Zhang, Q., Zhang, T., Li, J., Zhang, J., Hou, J., Liew, C. and Yin, D. (2007), Transcriptional silencing of the TMS1/ASC tumour suppressor gene by an epigenetic mechanism in hepatocellular carcinoma cells. J. Pathol., 212: 134–142. doi: 10.1002/path.2173
No conflicts of interest were declared.
- Issue published online: 11 MAY 2007
- Article first published online: 30 APR 2007
- Manuscript Accepted: 9 MAR 2007
- Manuscript Revised: 26 JAN 2007
- Manuscript Received: 5 NOV 2006
- Research Grant Committee, Hong Kong. Grant Number: CUHK4066/02M (2140319)
- Specialized Research Fund for the Doctoral Program of Higher Education, People's Republic of China. Grant Number: 20020422042
- DNA methylation;
- histone acetylation;
- histone methylation;
- hepatocellular carcinoma;
- TMS1 gene
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.