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.