Histone deacetylase inhibitors (HDACi) are small molecules that increase acetylation of lysine residues by ultimately inhibiting the activity of histone deactylase enzymes. These anticancer agents affect epigenetic and non-epigenetic regulation resulting in cell cycle arrest of cancer cell lines. We have conducted high throughput screen to elucidate effect of short term exposure to Trichostatin A on transcriptional activity of a model cell line. We have tested short term exposure (2h) of Trichostatin A (10uM) on ARPE-19 cell line.
In effort to define the molecular signature of TSA we have conducted downstream analyses of transcriptional expression. We have selected genes that showed at least 1.5 fold expression change and were significant (p<0.01). We identified 140 genes that were upregulated and 138 were downregulated. We observe a highly significant enrichment of genes involved dysregulation of p53 pathway (p-value 0.00001). Furthermore we observe a highly significant dysregulation of CREBBP pathway - a protein encoded by this gene has intrinsic histone acetyltransferase activity and also acts as a scaffold to stabilize additional protein interactions with the transcription complex. CREBBP autoacetylation is required for binding to protein substrates, such as acetylated histones and acetylated TP53/p53. KEGG pathways reports aberration of JAK-STAT pathway as well as signaling of Fibroblast Growth Factor Receptor 3 (FGFR3). Using this gene signature further disease perturbation result in a upregulated signature similar to that of Diamond-Blackfan anaemia (p=1.681e-11, OR=8.35). As an independent confirmation we find similar dysregulation patterns as caused by TSA (p=4.8e-86) from other deposited experiments within GEO Omnibus.
These preliminary signatures offer a glance into the transcriptional landscape as elicited by short-term exposure to TSA. Further experiments warrant a more comprehensive observations into the mode of action as well as biomarkers that may be useful to design optimal, TSA-based treatments.
Przychodzen:Vanda Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Smieszek:Vanda Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Polymeropoulos:Vanda Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Polymeropoulos:Vanda Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.
Asterisk with author names denotes non-ASH members.