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AP-2 regulates the transcription of estrogen receptor (ER)-β by acting through a methylation hotspot of the 0N promoter in prostate cancer cells

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Abstract

We reported previously that the loss of expression of estrogen receptor (ER)-β during the development of prostate cancer (PCa) is associated with methylation of a CpG island located in the 5′-flanking sequence of the 0N promoter. Three methylation hotspots, referred to as centers 1, 2 and 3, were identified in the CpG island. In this study, we demonstrated that a 581-bp region with these three centers within it is sufficient for the promoter activity in PCa cells. Deletion analyses indicated that center 1 (16 bp), with a putative activator protein-2 (AP-2) binding site, is essential for gene transactivation. Chromatin immunoprecipitation assays showed that AP-2α occupies a short sequence containing center 1. Forced expression of AP-2α or -2γ, but not -2β, increased activity of the ERβ 0N promoter and the accumulation of mRNA. Conversely, siRNA-mediated AP-2α and -2γ knockdown reduced levels of ERβ transcript and promoter activity. Quantitative reverse transcription–PCR showed that AP-2α and -2γ are the predominant transcripts expressed in PCa cells, and levels of ERβ transcript correlate with levels of these AP-2 transcripts among different PCa cell lines. These results provide the first evidence that ERβ is an AP-2-regulated gene. They also support the hypothesis that certain cis-acting elements are methylation hotspots susceptible to epigenetic modifications during cancer progression.

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Acknowledgements

We thank Dr Frederick E Domann for providing AP-2 expression plasmids. This work was supported in part by grants from the National Institutes of Health (DK061084 to SM Ho) and the Department of Defense (DAMD-W81XWH-04-1-0165 to SM Ho and W81XWH-06-1-0376 to X Zhang). Part of the work was conducted in the Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01605, USA.

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  1. Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    X Zhang, Y-K Leung & S-M Ho

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  1. X Zhang
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  2. Y-K Leung
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Correspondence to S-M Ho.

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Zhang, X., Leung, YK. & Ho, SM. AP-2 regulates the transcription of estrogen receptor (ER)-β by acting through a methylation hotspot of the 0N promoter in prostate cancer cells. Oncogene 26, 7346–7354 (2007). https://doi.org/10.1038/sj.onc.1210537

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