Histone deacetylase inhibitors as potential anti-skin cancer agents

The regulation of squamous differentiation is a tightly regulated process involving transcriptional repression and activation. Previous studies have established 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 disrupt 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 carcinoma cells in tissue culture. We found that treatment of keratinocytes or squamous carcinoma cells with butyrate induced a reversible growth arrest. TSA, on the other hand, induced an irreversible growth arrest in both keratinocytes and squamous carcinoma cells. The growth arrest of keratinocytes induced by TSA or butyrate was accompanied by a reduction in the mRNA levels for proliferation gene cdk1 and an induction of the mRNA for the differentiation-specific transglutaminase type I gene (TG1). In contrast, the squamous carcinoma cells had decreased cdk1 and TG1 mRNA in response to TSA or butyrate. Both of these agents produced transient increases in the acetylation of histone H4 in keratinocytes and squamous carcinoma cells. These data indicated that TSA may have potential as a topical treatment for epidermal malignancies.