Synergistic Activation of Functional Estrogen Receptor (ER)-{alpha} by DNA Methyltransferase and Histone Deacetylase Inhibition in Human ER-{alpha}-negative Breast Cancer Cells

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Synergistic Activation of Functional Estrogen Receptor (ER)- ${alpha}$ by DNA Methyltransferase and Histone Deacetylase Inhibition in Human ER- ${alpha}$ -negative Breast Cancer Cells¹

Xiaowei Yang², Dawn L. Phillips, Anne T. Ferguson³, William G. Nelson, James G. Herman and Nancy E. Davidson⁴

The Johns Hopkins Oncology Center, Johns Hopkins University, Baltimore, Maryland 21231

Formation of transcriptional repression complexes such as DNAmethyltransferase (DNMT) 1/histone deacetylase (HDAC) or methyl-CpGbinding protein/HDAC is emerging as an important mechanism insilencing a variety of methylated tissue-specific and imprintedgenes. Our previous studies showed that treatment of estrogenreceptor (ER)- ${alpha}$ -negative human breast cancer cells with the DNMTinhibitor 5-aza-2'-deoxycytidine (5-aza-dC) led to ER mRNA andprotein re-expression. Also, the HDAC inhibitor trichostatinA (TSA) could induce ER transcript about 5-fold. Here we showthat 5-aza-dC alone induced ER transcript about 30–40-fold,and the addition of TSA elevated ER mRNA expression about 10-foldmore in the human ER-negative breast cancer cell lines MDA-MB-231and MDA-MB-435. Overall, the combination of 5-aza-dC and TSAinduced a 300–400-fold increase in ER transcript. Restorationof estrogen responsiveness was demonstrated by the ability ofthe induced ER protein to elicit estrogen response element-regulatedreporter activity from an exogenous plasmid as well as induceexpression of the ER target gene, progesterone receptor. Thesynergistic activation of ER occurs concomitantly with markedlyreduced soluble DNMT1 expression and activity, partial demethylationof the ER CpG island, and increased acetylation of histonesH₃ and H₄. These data suggest that the activities of both DNMT1and HDAC are key regulators of methylation-mediated ER genesilencing.

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