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

  • 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.

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Author:Laura Pufahl, Careen Katryniok, Nicole Schnur, Bernd Lothar Sorg, Julia MetznerGND, Manuel GrezGND, Dieter SteinhilberORCiDGND
Pubmed Id:
Parent Title (English):Journal of cellular and molecular medicine
Place of publication:Hoboken, NJ
Document Type:Article
Date of Publication (online):2012/06/28
Date of first Publication:2012/06/28
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2013/02/08
Tag:5-lipoxygenase; chromatin immunoprecipitation; epigenetics; histone acetylation; histone deacetylase inhibitor; trichostatin A
Page Number:13
First Page:1461
Last Page:1473
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. This is an Open Access article under the terms of the Creative Commons Attribution Non Commercial License which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell 3.0