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We aimed to elucidate the epigenetic mechanisms involved in <jats:italic>MDR1<\/jats:italic> deregulation in PCa.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>\n              <jats:italic>MDR1<\/jats:italic> promoter methylation and P-gp expression were assessed in 121 PCa, 39 high-grade prostatic intraepithelial neoplasia (HGPIN), 28 benign prostatic hyperplasia (BPH) and 10 morphologically normal prostate tissue (NPT) samples, using quantitative methylation specific PCR and immunohistochemistry, respectively. PCa cell lines were exposed to a DNA methyltransferases inhibitor 5-aza-2\u2032deoxycytidine (DAC) and histone deacetylases inhibitor trichostatin A (TSA). Methylation and histone posttranscriptional modifications status were characterized and correlated with mRNA and protein expression. <jats:italic>MDR1<\/jats:italic> promoter methylation levels and frequency significantly increased from NPTs, to HGPIN and to PCa. Conversely, decreased or absent P-gp immunoexpression was observed in HGPIN and PCa, inversely correlating with methylation levels. Exposure to DAC alone did not alter significantly methylation levels, although increased expression was apparent. However, P-gp mRNA and protein re-expression were higher in cell lines exposed to TSA alone or combined with DAC. Accordingly, histone active marks H3Ac, H3K4me2, H3K4me3, H3K9Ac, and H4Ac were increased at the <jats:italic>MDR1<\/jats:italic> promoter after exposure to TSA alone or combined with DAC.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Our data suggests that, in prostate carcinogenesis, <jats:italic>MDR1<\/jats:italic> downregulation is mainly due to histone post-translational modifications. This occurs concomitantly with aberrant promoter methylation, substantiating the association with P-gp decreased expression.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2164-14-898","type":"journal-article","created":{"date-parts":[[2013,12,17]],"date-time":"2013-12-17T12:00:57Z","timestamp":1387281657000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Epigenetic regulation of MDR1 gene through post-translational histone modifications in prostate cancer"],"prefix":"10.1186","volume":"14","author":[{"given":"Rui","family":"Henrique","sequence":"first","affiliation":[]},{"given":"Ana Isabel","family":"Oliveira","sequence":"additional","affiliation":[]},{"given":"Vera L","family":"Costa","sequence":"additional","affiliation":[]},{"given":"Tiago","family":"Baptista","sequence":"additional","affiliation":[]},{"given":"Ana Teresa","family":"Martins","sequence":"additional","affiliation":[]},{"given":"Ant\u00f3nio","family":"Morais","sequence":"additional","affiliation":[]},{"given":"Jorge","family":"Oliveira","sequence":"additional","affiliation":[]},{"given":"Carmen","family":"Jer\u00f3nimo","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2013,12,17]]},"reference":[{"issue":"5","key":"5584_CR1","doi-asserted-by":"publisher","first-page":"621","DOI":"10.2174\/138945011795378540","volume":"12","author":"S Shukla","year":"2011","unstructured":"Shukla S, Ohnuma S, Ambudkar SV: Improving cancer chemotherapy with modulators of ABC drug transporters. 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