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 equilibrium of histone acetyl-transferase activity (HAT) and the histone deacetylase activity (HDAC). Commonly, DNA-transfection assays are used to measure the effect of histone acetylation and deacetylation on gene transcription. Here we have analyzed the response of various viral long terminal repeats and vertebrate promoters to the specific histone deacetylase inhibitor trichostatin A (TSA). We show that the activity of many, but not all, promoters is increased upon TSA treatment. Interestingly, the lysozyme promoter exhibited TSA resistance, while the activity of metallothionine, the human growth hormone, and the thymidine kinase promoters was increased. Furthermore, we found that all tested viral promoters are induced by TSA. Analysis of the transcriptional behaviour of the thyroid hormone receptor (TR), the cellular homologue of the v-erbA oncogene, revealed that TSA reduced the gene silencing function but had no influence on the hormone-induced gene activation function of the receptor. These results on gene specific effects, together with the HDAC structural data (1), may be a basis for the development of HDAC inhibitors as antitumor agents.
Dressel
U
U
Genetic Institute, Justus-Liebig-University, Giessen, Germany.
Renkawitz
R
R
Baniahmad
A
A
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D005914:Globins / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007668:Kidney; D008156:Luciferases / Q000235:genetics; D008668:Metallothionein / Q000235:genetics; D011401:Promoter Regions, Genetic; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D011994:Recombinant Proteins / Q000096:biosynthesis; D013937:Thymidine Kinase / Q000235:genetics; D015533:Transcriptional Activation; D014162:Transfection
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011988:Receptors, Thyroid Hormone; D011994:Recombinant Proteins; C012589:trichostatin A; D005914:Globins; D008668:Metallothionein; D008156:Luciferases; D015500:Chloramphenicol O-Acetyltransferase; D013937:Thymidine Kinase; D006655:Histone Deacetylases