Promoter specific sensitivity to inhibition of histone deacetylases: Implications for hormonal gene control, cellular differentiation and cancer

Alterations in histone acetylation status appear to play a central role in the regulation of neoplasia, tumor suppression, cell cycle control, hormone responsiveness and senescence. These alterations of chromatin control gene transcription. The histone acetylation status is regulated by the equilibr ium of histone acetyl-transferase activity (HAT) and the histone deacetylas e activity (HDAC). Commonly, DNA-transfection assays are used to measure th e effect of histone acetylation and deacetylation on gene transcription. He ra we have analyzed the response of various viral long terminal repeats and vertebrate promoters to the specific histone deacetylase inhibitor trichos tatin A (TSA). We show that the activity of many, but not all, promoters is increased upon TSA treatment. Interestingly, the lysozyme promoter exhibit ed TSA resistance, while the activity of metallothionine, the human growth hormone, and the thymidine kinase promoters was increased. Furthermore, we found that all tested virus promoters are induced by TSA. Analysis of the t ranscriptional behaviour of the thyroid hormone receptor (TR), the cellular homologLre of the v-erbA oncogene, revealed that TSA reduced the gene sile ncing function but had no influence on the ho,hormone-induced gene activati on function of the receptor: These results an gene specific effects, togeth er with the HDAC structural data (1), may be a basis for the development of HDAC inhibitors as antitumor agents.