Death Receptor 6 is Epigenetically Silenced by Histone Deacetylation in Endometriosis and Promotes the Pathogenesis of Endometriosis
Death Receptor 6 is Epigenetically Silenced by Histone Deacetylation in Endometriosis and Promotes the Pathogenesis of Endometriosis
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DOI：
10.1111/aji.12155
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发表时间：
2013-12-01
影响因子：
3.6
通讯作者：
Narahara, Hisashi
中科院分区：
文献类型：
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作者：
Kai, Kentaro;Nasu, Kaei;Narahara, Hisashi
本研究旨在探讨死亡受体(DR)6在子宫内膜异位症发病机制中的作用。方法分别从卵巢异位内膜组织和在位内膜组织分离子宫内膜异位囊间质细胞(ECSCs)和正常子宫内膜基质细胞(NESCs)。观察丙戊酸(VPA)对内皮干细胞DR6表达的影响。以DR6 siRNA为靶点，研究DR6在NESC增殖和凋亡中的作用。采用免疫组织化学方法检测DR6蛋白在卵巢异位内膜和正常增生期子宫内膜中的分布。结果Death受体6在eCSCs和子宫内膜异位症组织中的表达均减弱，VPA刺激后其表达上调。VPA处理导致DR6基因启动子区域乙酰化组蛋白H4的积累。结论DR6基因表达下调可能通过产生子宫内膜异位症的增殖和抗凋亡特性而参与子宫内膜异位症的发病机制。研究结果还表明，组蛋白脱乙酰酶抑制剂是治疗子宫内膜异位症的有前途的药物。
ProblemThe purpose of this study is to evaluate the involvement of death receptor (DR) 6 in the pathogenesis of endometriosis.Methods of studyEndometriotic cyst stromal cells (ECSCs) and normal endometrial stromal cells (NESCs) were isolated from ovarian endometriotic tissues and the eutopic endometrial tissues, respectively. The effect of valproic acid (VPA) on the DR6 expression in ECSCs was examined. The roles of DR6 in NESC proliferation and apoptosis were investigated with DR6 siRNA transfection. The distribution of DR6 protein in ovarian endometriotic tissues and normal proliferative-phase endometrium was examined by immunohistochemistry. The expression of DR6 mRNA and protein in ECSCs and NESCs was also examined.ResultsDeath receptor 6 expression was attenuated in ECSCs and in endometriotic tissues, and its expression was upregulated by VPA stimulation. VPA treatment resulted in an accumulation of acetylated histone H4 in the promoter region of the DR6 gene. DR6 knockdown directed the stimulation of cell proliferation and the resistance to apoptosis in NESCs.ConclusionThe present findings suggested that DR6 is involved in the pathogenesis of endometriosis by creating the proliferative and anti-apoptotic characteristics of endometriosis. The results also suggest that histone deacetylase inhibitors are promising agents for the treatment of endometriosis.