Histone deacetylase inhibitors as potential anti-skin cancer agents

The regulation of squamous differentiation is a tightly regulated process i nvolving transcriptional repression and activation. Previous studies have e stablished that squamous carcinoma cell lines inappropriately regulate the transcription of genes important to the control of squamous differentiation . Histone deactylase inhibitors such as trichostatin A (TSA) and butyrate d isrupt normal chromatin structure and cause alterations in gene expression/ regulation. For these reasons, we examined the effects of both butyrate and TSA on the growth and differentiation of human keratinocytes or squamous c arcinoma cells in tissue culture. We found that treatment of keratinocytes or squamous carcinoma cells with butyrate induced a reversible growth arres t. TSA, on the other hand, induced an irreversible growth arrest in both ke ratinocytes and squamous carcinoma cells. The growth arrest of keratinocyte s induced by TSA or butyrate was accompanied by a reduction in the mRNA lev els for proliferation gene cdk1 and an induction of the mRNA for the differ entiation-specific transglutaminase type I gene (TG1). In contrast, the squ amous carcinoma cells had decreased cdk1 and TG1 mRNA in response to TSA or butyrate, Both of these agents produced transient increases in the acetyla tion of histone H4 in keratinocytes and squamous carcinoma cells. These dat a indicated that TSA may have potential as a topical treatment for epiderma l malignancies.