Abstract
BackgroundEukaryotic gene expression is a complex process involving multiple cis and trans activating molecules to either facilitate or inhibit transcription. In recent years, many studies have focused on the role of acetylation of histone proteins in modulating transcription, whereas deacetylation of these same proteins is associated with inactivation or repression of gene expression. This study explores gene expression in HepG2 and F9 cell lines treated with Trichostatin A (TSA), a potent histone deacetylase inhibitor.ResultsThese experiments show that TSA treatment results in clear repression of genes involved in the cholesterol biosynthetic pathway as well as other associated pathways including fatty acid biosynthesis and glycolysis. TSA down regulates 9 of 15 genes in this pathway in the F9 embryonal carcinoma model and 11 of 15 pathway genes in the HepG2 cell line. A time course study on the effect of TSA on gene expression of various enzymes and transcription factors involved in these pathways suggests that down regulation of Srebf2 may be the triggering factor for down regulation of the cholesterol biosynthesis pathway.ConclusionOur results provide new insights in the effects of histone deacetylases on genes involved in primary metabolism. This observation suggests that TSA, and other related histone deacetylase inhibitors, may be useful as potential therapeutic entities for the control of cholesterol levels in humans.
Highlights
Eukaryotic gene expression is a complex process involving multiple cis and trans activating molecules to either facilitate or inhibit transcription
In a previous study looking at the combination regimen of all trans retinoic acid (RA) with the Histone deacetylase inhibitors (HDACIs), Trichostatin A (TSA), we identified several new targets for HDACIs [18]
We found down regulated genes involved in pyrimidine biosynthesis (Dhodh) and in the cholesterol metabolism pathway (Mvk, lanosterol synthase (Lss), HMG CoA reductase (Hmgcr), fatty acid synthase (Fasn) and squalene epoxidase (Sqle)) (Figure 2)
Summary
Eukaryotic gene expression is a complex process involving multiple cis and trans activating molecules to either facilitate or inhibit transcription. HDACIs have been shown to induce differentiation, apoptosis or growth arrest in a variety of transformed cell lines [5]. This is generally attributed to the ability of these inhibitors to induce an open chromatin conformation facilitating transcription of regulatory genes like p21 which inhibit tumor cell growth [6]. These qualities make HDACIs promising targets for chemotherapeutic intervention
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