Pax5 Re-Expression In H460 Cells Treated With The Combination Of Demethylating Agent And Histone Deacetylase Inhibitor Is Associated With The Enhancement Of P53 Binding To Pax5 Promoter Region.

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Pax5 Re-Expression In H460 Cells Treated With The Combination Of Demethylating Agent And Histone Deacetylase Inhibitor Is Associated With The Enhancement Of P53 Binding To Pax5 Promoter Region.

Curr Cancer Drug Targets. 2016 Mar 31;

Authors: Liang Y, Zeng J, Jelicks L, Ma S, Liu J, Mei J, Perez-Soler R, Zou Y

Abstract
The epigenetic combinations of DNA demethylating agents and histone deacetylase (HDAC) inhibitors have demonstrated clinical benefits for non-small cell lung cancer (NSCLC) treatment, however, there are few studies uncovering the underlying molecular mechanism of the combinations. Our previous study showed that DNA demethylating agent Azacitidine (Aza) demethylated CpG sites in paired box gene 5 (pax5) promoter region, but did not induce pax5 mRNA or protein expression. In this study, we used epigenetic combination of Aza and HDAC inhibitor Vorinostat (SAHA) to treat NSCLC cells and tried to elucidate the underlying molecular mechanism. We treated pax5-silenced NSCLC H460 cells with Aza+SAHA combination at sub-toxic concentration and detected the re-expression of pax5 mNRA and protein. Our MassArray illustrated demethylation of CpG sites in pax5 promoter region by Aza treatment; and DNA-protein binding assay indicated increased DNA accessibility for protein binding by SAHA treatment. Chromatin DNA-protein binding test demonstrated that the combination of Aza+SAHA significantly increased p53 protein binding to DNA in pax5 promoter region (p<0.01). These results implied more efficient binding of the transcription factor p53 to pax5 promoter region likely because SAHA increased accessibility of the chromatin conformation and Aza-demethylated DNA was more permissive, allowing transcription factors to bind. Our study not only explained an underlying mechanism, that pax5 re-expression was induced by Aza+SAHA combination in H460 cells via p53, but also demonstrated a pattern showing that the combination of demethylating agent and HDAC inhibitor can re-activate tumor suppressor gene (TSG) which is associated with the enhancement of transcription factors binding to the promoter region of the TSG.

PMID: 27029827 [PubMed - as supplied by publisher]

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