Trichostatin A induces 5‐lipoxygenase promoter activity and mRNA expression via inhibition of histone deacetylase 2 and 3

• Published in: Journal of cellular and molecular medicine Vol. 16; no. 7; pp. 1461 - 1473
• Main Authors: Pufahl, Laura, Katryniok, Careen, Schnur, Nicole, Sorg, Bernd L., Metzner, Julia, Grez, Manuel, Steinhilber, Dieter
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2012; John Wiley & Sons, Inc
• Subjects: 5‐lipoxygenase; Acetylation; Acetylation - drug effects; Arachidonate 5-lipoxygenase; Arachidonate 5-Lipoxygenase - genetics; Arachidonate 5-Lipoxygenase - metabolism; Benzamides - pharmacology; Biotechnology; Calcium phosphates; Cell lines; Chromatin; Chromatin Immunoprecipitation; DNA methylation; DNA-directed RNA polymerase; epigenetics; Gene expression; Gene regulation; HDAC2 protein; histone acetylation; Histone deacetylase; Histone Deacetylase 1 - antagonists & inhibitors; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - metabolism; Histone Deacetylase 2 - genetics; Histone Deacetylase 2 - metabolism; histone deacetylase inhibitor; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histone H3; Histones - genetics; Histones - metabolism; HL-60 Cells; Humans; Hydroxamic Acids - pharmacology; Immunoprecipitation; Leukotrienes; Lipoxygenase; Methylation; Original; Penicillin; Peptides, Cyclic - pharmacology; Plasmids; Promoter Regions, Genetic; Proteins; Pyridines - pharmacology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation; Trichostatin A; U937 Cells; Up-Regulation; Germany
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/j.1582-4934.2011.01420.x

The 5‐lipoxygenase (5‐LO) is the key enzyme in the formation of leukotrienes. We have previously shown that the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) activates 5‐LO transcription via recruitment of Sp1, Sp3 and RNA polymerase II to the proximal promoter. To identify the HDACs involved in the regulation of 5‐LO promoter activity isoform‐specific HDAC inhibitors were applied. 5‐LO promoter activity and mRNA expression were up‐regulated by the class I HDAC inhibitors apicidin and MS‐275 but not by class II inhibitors. Knockdown of HDAC 1, 2 and 3 revealed that HDAC2 and HDAC3 but not HDAC1 is involved in the up‐regulation of 5‐LO mRNA expression. To analyse the chromatin modifications at the 5‐LO promoter associated with HDAC inhibition, the time course of 5‐LO mRNA induction by trichostatin A was investigated and the concomitant changes in histone modifications at the 5‐LO promoter in HL‐60, U937 and Mono Mac6 cells were determined. Chromatin immunoprecipitation analysis revealed that trichostatin A increases acetylation of histones H3 and H4 at the 5‐LO core promoter in HL‐60 and U937 cells whereas no significant changes were observed in Mono Mac6 cells. The appearance of H3 and H4 acetylation preceded the 5‐LO mRNA induction whereas in all three cell lines, induction of 5‐LO mRNA expression correlated with histone H3 lysine 4 trimethylation (H3K4me3), a marker for transcriptional activity of gene promoters.