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 inv...
Gespeichert in:
Veröffentlicht in: | Journal of cellular and molecular medicine 2012-07, Vol.16 (7), p.1461-1473 |
---|---|
Hauptverfasser: | , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext bestellen |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | 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. |
---|---|
ISSN: | 1582-1838 1582-4934 |
DOI: | 10.1111/j.1582-4934.2011.01420.x |