Ken Tachibana

Correlation between histone acetylation and expression of the MYO18B gene in human lung cancer cells

Recently, we isolated a candidate tumor‐suppressor gene, MYO18B, which was inactivated in approximately 50% of human lung cancers by deletion, mutation, and promoter methylation. However, more frequent reduction or loss of MYO18B expression and restoration of MYO18B expression by trichostatin A (TSA) treatment suggested the contribution of other mechanisms, especially histone deacetylation, for epigenetic inactivation of the MYO18B gene. In this study, we examined histone modification of the promoter region of the MYO18B gene in 8 human lung cancer cell lines by a chromatin immunoprecipitation assay. In 6 of 7 cell lines with reduced or silenced MYO18B expression, the levels of histones H3 and H4 acetylation surrounding the MYO18B promoter region were lower than those in a cell line with MYO18B expression. By treatment with TSA, the levels of histone H3 and H4 acetylation were increased in all 6 cell lines whose MYO18B expression was restored by TSA, whereas neither H3 nor H4 acetylation was increased in cells whose MYO18B expression was not restored by TSA. Significant correlations were observed between the levels of histone H3/H4 acetylation and MYO18B expression. These results suggest that acetylation of both histones H3 and H4 contributes to regulation of MYO18B expression in lung cancer cells and that histone deacetylation surrounding the promoter region plays an important role in MYO18B silencing and is involved in lung carcinogenesis.

Staurosporine enhances the expression of tissue inhibitor of metalloproteinase-1 in human prostate cancer cells

We reported previously that human prostate cancer cell line TSU-Pr1 can differentiate into neuronal cells by staurosporine treatment. In this process, reduction of invasive abilities was observed in staurosporine treated TSU-Pr1 cells. In the present study, we investigated the effect of staurosporine on tissue inhibitor of metalloproteinases (TIMPs) in prostate cancer cells. We show that treatment of TSU-Pr1 cells with staurosporine results in induction of TIMP-1 mRNA and protein secretion. The induction of TIMP-1 mRNA expression by staurosporine is likely to be caused by increased transcriptional activity and this mechanism is indirect. Furthermore, recombinant human TIMP-1 reduces the invasive activity of TSU-Pr1 cells. We are the first to report that mRNA expression and protein secretion of TIMP-1 are enhanced by staurosporine treatment in prostate cancer cells. These findings suggest that enhancement of TIMP-1 is associated with suppression of invasive activity caused by staurosporine treatment.

Treatment of tumor cells with histone deacetylase inhibitors results in altered recruitment of methyl-CpG binding proteins to a methylated CpG island.

Abstract When human cancer cells with silencing of the CDH1 gene associated with CpG island methylation and histone deacetylation were treated with histone deacetylase inhibitors, alteration in recruitment of methyl-CpG binding proteins (MBPs) to the methylated CDH1-CpG island was observed, as well as altered histone acetylation status. This change was independent of the histone deacetylase inhibitor used. These results suggest that histone hyperacetylation provides a more open chromatin structure conformation for the recruitment of additional MBPs.