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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

Oncogene volume 26, pages 7346–7354 (2007)Cite this article

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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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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