ROLE OF LYSINE DEACETYLASES IN GLUCOCORTICOID RECEPTOR-MEDIATED TRANSCRIPTIONAL REPRESSION

Maryam Gilpatrick , Vineela Kadiyala, An Lingling, Catharine L. Smith

ROLE OF LYSINE DEACETYLASES IN GLUCOCORTICOID RECEPTOR-MEDIATED TRANSCRIPTIONAL REPRESSION

Lysine deacetylases (KDACs) are known drug targets undergoing evaluation in several clinical trials for their use in the treatment of cancer and other diseases. It is therefore essential to understand KDACs’ role in transcription and signaling to reveal the full cellular effects of KDAC inhibitors (KDACi). Our study’s goal is to determine the role of lysine deacetylases (KDACs) in glucocorticoid-regulator mediated transcriptional activation and repression. We carried out expression profiling studies in a GC responsive hepatoma-derived cell line and found that VPA, a class I-selective KDACi, has profound impact on the GR-regulated hepatic transcriptome. VPA alone mimics GR signaling at some target genes and co-operates with GR at others to active expression. However, its dominant effect is the impairment of normal activation, which suggests that KDACs play a significant role in facilitating GC signaling. Our current studies involve determining which Class I KDACs are involved in direct transcriptional regulation through siRNA knockdown.

Funding: Bio5 Institute; Rescorp; NSF MCB-1122088

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