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

Journal of Cellular and Molecular Medicine

Laura Pufahl¹  Careen Katryniok¹  Nicole Schnur¹  Bernd L. Sorg¹  Julia Metzner¹  Manuel Grez² 

[1] Institute of Pharmaceutical Chemistry/ZAFES, Goethe University Frankfurt, Frankfurt, Germany;Georg-Speyer-Haus, Frankfurt, Germany

关键词: 5‐lipoxygenase;    epigenetics;    histone deacetylase inhibitor;    trichostatin A;    chromatin immunoprecipitation;    histone acetylation;   

DOI  :  10.1111/j.1582-4934.2011.01420.x

来源: Wiley

【 摘 要 】

Abstract

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.

【 授权许可】

Unknown   
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd