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

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.

CD1d induction in solid tumor cells by histone deacetylase inhibitors through inhibition of HDAC1/2 and activation of Sp1

“…HDAC inhibition relieves the repression of HDACs from Sp1 sites and recruits CBP/ p300 that possess intrinsic HAT activity, leading to the acetylation of surrounding histones and the enrichment of RNA polymerase II to initiate gene transcription. [27][28][29][30] Our previous study also demonstrates that abrogation of HDAC activity by Figure 4. Effects of sAhA, ATRA and 9cRA on RARE3-tk-luc reporter activity in A549 cells.…”

Inhibitors of Histone Deacetylases Enhance Neurotoxicity of DNA Damage

“…Conversely, MS275 is ineffective against class II HDACs (Khan et al 2008). In our experiments, MS275 was used at 1 μM; in another cell culture study, such a concentration has been relatively ineffective against HDAC2 and HDAC3 (Pufahl et al 2012). Therefore, inability of MS275 to modify p53 activation in DSB-challenged neurons suggests involvement of HDAC2 and/ or HDAC3 and/or class II HDACs.…”

Epigenetic Regulation of Cytosolic Phospholipase A2 in SH-SY5Y Human Neuroblastoma Cells

“…Besides inhibiting histone deacetylation, TSA is also known to induce trimethylation of H3K4 to cause transcriptional activation of genes [29,30,55,83]. Since trimethylated H3K4 is often associated with acetylated H3K9 histones in activated genes [30], we investigated the possibility of increased H3K4 trimethylation after TSA treatment.…”