Effects of demethylating agent 5-aza-2(′)-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines, Oral Oncol

Summary Maspin, which belongs to the serine protease inhibitor (serpin) superfamily, has been proposed as a potent tumor suppressor that inhibits cell motility, invasion, angiogenesis, and metastasis. In the present study, we examined the effects of 5-Aza-2'-deoxycytidine (5-Aza-dC), a demethylating agent, and FR901228, a histone deacetylase (HDAC) inhibitor, on maspin expression in oral cancer cell lines. The expression levels of maspin mRNA were divided into two groups, which was the maspin low-expressed and high-expressed cell lines in the 12 oral cancer cell lines. The maspin promoter contained only a few methylated CpG sites in the maspin low-expressed cell lines. Moreover, the methylation status was not altered after 5Aza-dC treatment. However, the transcription of the maspin gene was clearly increased following 5Aza-dC treatment in a number of oral cancer cell lines. These results imply that an action of 5Aza-dC is separate from induction of promoter demethylation. Treatment with FR901228 resulted in a time-dependent stimulation of the re-expression of maspin mRNA as early as 4 hours after treatment in the maspin downregulated cells. The re-expression of the maspin gene may contribute to the recuperation of biological functions linked to FR901228 such as an inhibitory effect on tumor angiogenesis and cell invasion. These results indicate that maspin and its target genes may be excellent leads for future studies on the potential benefits of FR901228, a histone deacetylase inhibitor, in cancer therapy