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Research Paper
Histone Deacetylase Inhibitor LBH589 Reactivates Silenced Estrogen Receptor Alpha (ER) Gene Expression without Loss of DNA Hypermethylation
Qun Zhou, Peter Atadja and Nancy E. Davidson
volume 6 | issue 1
January 2007Pages: 64 - 69
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Our previous studies demonstrated that inhibition of histone deacetylases (HDACs) by trichostatin A reactivates estrogen receptor alpha (ER) gene expression in ER-negative breast cancer cells. Here, we use the clinically relevant HDAC inhibitor, LBH589 (LBH) to explore the roles of HDAC in ER gene silencing. In the ER-negative human breast cancer lines, MDA-MB-231 and MDA-MB-435, treatment with LBH for 24 hours restored ER mRNA and protein expression without a concomitant demethylation of the CpG island at the ER promoter. The expression of ER mRNA was sustained at least 96 hours after withdrawal of LBH treatment. Restoration of ER expression by LBH enhanced 4-hydroxytamoxifen sensitivity in MDA-MB-231 cells. The molecular mechanisms by which LBH reactivated silenced ER gene in MDA-MB-231 cells were examined with emphasis on chromatin structure reorganization. By chromatin immunoprecipitation analysis, LBH treatment released DNMT1, HDAC1, and the H3 (Lys-9) methyltransferase SUV39H1 from the ER promoter. Such changes were associated with an active chromatin formation manifested as accumulation of acetylated histones H3 and H4, a decrease in methylated H3 lysine 9 (H3-K9), and an impaired binding of heterochromatin protein 1 (HP1α) at the promoter. Our findings suggest that HDAC inhibitors could restore expression of the silenced ER gene by reorganizing the heterochromatin-associated proteins without alteration in promoter DNA hypermethylation.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.