Histone deacetylase inhibitors: a new mode for inhibition of cholesterol metabolism.
BACKGROUND
Eukaryotic 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.


RESULTS
These 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.


CONCLUSIONS
Our 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.
Chittur
Sridar V
SV
Center for Functional Genomics, University at Albany, State University of New York, Cancer Research Center, One Discovery Drive, Rm 310, Rensselaer, NY 12144, USA. schittur@albany.edu
Sangster-Guity
Niquiche
N
McCormick
Paulette J
PJ
D000107:Acetylation; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D004791:Enzyme Inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D053858:Metabolic Networks and Pathways / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics*
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; C012589:trichostatin A; D002784:Cholesterol