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Promoter Hypermethylation of Progesterone Receptor Isoform B (PR-B) in Adenomyosis and Its Rectification by a Histone Deacetylase Inhibitor and a Demethylation Agent

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Abstract

Adenomyosis is a fairly common gynecologic disease with unknown pathogenesis. We sought to investigate as to whether the promoter of progesterone receptor isoform B (PR-B) is hypermethylated in adenomyosis and to investigate the treatment of ectopic endometrial stromal cells with trichostatin A (TSA), a histone deacetylase inhibitor (HDI), and 5-aza-2-deoxycytidine (ADC), a demethylation agent, on PR-B gene and protein expression, and on cell viability. Ectopic endometrial tissue specimens were obtained from 9 women with adenomyosis whereas control endometrial tissue samples were obtained from 8 women with surgically diagnosed benign ovarian cysts but without any clinical history of endometriosis/adenomyosis/myoma. Endometrial stromal cells were isolated, purified, cultured, and analyzed by methylation-specific polymerase chain reaction (PCR), real-time reverse transcriptase PCR (RT-PCR), and Western blot analysis, cell viability assays, and fluorescence-activated cell sorting. We found that none of the normal endometrial stromal cells had PR-B promoter methylation. In contrast, 2 out of 3 ectopic endometrial stromall cells had PR-B hypermethylation (P <.05). The treatment with both TSA and ADC elevated PR-B gene and protein expression in ectopic, but not in normal, endometrial stromal cells. Both TSA and ADC treatment dose-dependently reduced cell viability of ectopic endometrial stromal cells. Trichostatin A and ADC treatment also suppressed the cell cycle progression in ectopic endometrial stromal cells. Thus, this study provides the first piece of evidence that adenomyosis has epigenetic aberration and may also be an epigenetic disease amenable to rectification by pharmacological means. This perspective may shed new light onto the pathogenesis of adenomyosis and lead to novel ways to treat the disease.

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Authors and Affiliations

  1. Shanghai Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai, 200011, China

    Jichan Nie MD, Xishi Liu MD, PhD & Sun-Wei Guo PhD

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  1. Jichan Nie MD
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  2. Xishi Liu MD, PhD
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Correspondence to Sun-Wei Guo PhD.

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Nie, J., Liu, X. & Guo, SW. Promoter Hypermethylation of Progesterone Receptor Isoform B (PR-B) in Adenomyosis and Its Rectification by a Histone Deacetylase Inhibitor and a Demethylation Agent. Reprod. Sci. 17, 995–1005 (2010). https://doi.org/10.1177/1933719110377118

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