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

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.

Mechanisms of Resistance to Histone Deacetylase Inhibitors and Their Therapeutic Implications

“…Furthermore, cases in which either treatment alone was insufficient to induce significant reexpression of epigenetically silenced genes have been reported. Among those, synergistic reexpression of the MAGE family in testicular cancers and TMSC1 in hepatocellular carcinoma occurs only in response to the combination of 5-aza-2 ¶-deoxycytidine and HDIs (25,26). Although emerging new data suggest that in some cases HDIs can affect global and gene-specific DNA methylation (27,28), most studies indicate that this repressive mark cannot be overcome by the single action of HDIs.…”

High expression of trimethylated histone H3 at lysine 27 predicts better prognosis in non-small cell lung cancer

“…The alterations in epigenomes such as DNA methylation and histone modifications play pivotal roles in carcinogenesis (2)(3)(4). It has been reported that DNA methylation level and global histone modification patterns may be possible predictors of cancer recurrence and prognosis in a large variety of cancer entities (5,6).…”

“…It has been reported that DNA methylation level and global histone modification patterns may be possible predictors of cancer recurrence and prognosis in a large variety of cancer entities (5,6). Post-translational modification of histone tails alters the physical state of chromatin and has an essential role in both transcriptional repression and activation during embryonic development, lineage specification, terminal differHigh expression of trimethylated histone H3 at lysine 27 predicts better prognosis in non-small cell lung cancer XIAOHUI CHEN 1,4 , NING SONG entiation and tumorigenesis as well (7,8). One such repressive modification, the trimethylation of lysine 27 on histone H3 (H3K27me3), seemed to be an epigenetic label mediating gene silencing; and a mark for de novo DNA methylation in cancer cells by recruitment of DNA methyltransferase (DNMTs) (9)(10)(11), contributing to tumor progression through suppression of a certain gene expression (12).…”

Relationship between Autoimmunity and Cancer or Metabolic Abnormality in Liver Diseases

“…Aberrant promoter methylation of the genes can directly lead to transcriptional inactivation and loss of gene function [47]. The methylation of tumor-associated genes may be involved in carcinogenesis [48][49][50] and may trigger the production of autoantibodies to TAAs (anti-TAAs).…”