Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Yufu-shi, Oita, Japan.
Hum Reprod. 2011 Sep;26(9):2486-98. doi: 10.1093/humrep/der203. Epub 2011 Jun 29.
Accumulating evidence suggests that various epigenetic aberrations play definite roles in the pathogenesis of endometriosis. We investigated the histone acetylation status in endometriosis and the application of the histone deacetylase inhibitors (HDACIs) for the treatment of endometriosis.
The levels of acetylated histones in the endometriotic cyst stromal cells (ECSCs) and normal endometrial stromal cells (NESCs) were evaluated. The effects of the HDACIs on cell proliferation, the cell cycle, apoptosis of ECSCs and NESCs, and the expression of genes related to these cellular events were investigated. The effects of HDACIs on histone acetylation in chromatin of the promoter region of the cell cycle regulatory genes in ECSCs were also investigated.
The acetylated histone levels were significantly lower in ECSCs than in NESCs (P < 0.025). HDACIs inhibited cell proliferation and induced cell cycle arrest and apoptosis of ECSCs. The effects of HDACIs on NESCs were marginal or weak. These HDACIs induced an accumulation of acetylated histones in total cellular chromatin and in the promoter regions of the p16(INK4a), p21(Waf1/Cip1), p27(Kip1) and cycle checkpoint kinase 2 genes in ECSCs. HDACIs induced the protein expression of these cell cycle regulators and suppressed the protein expression of Bcl-2 and Bcl-X(L) in ECSCs.
The present findings demonstrated that aberrant histone modifications are present in endometriosis and that HDACIs reactivated epigenetically silenced genes, resulting in the suppression of cell proliferation, induction of cell cycle arrest and apoptosis of ECSCs. HDACIs are therefore promising agents for the treatment of endometriosis.
越来越多的证据表明，各种表观遗传异常在子宫内膜异位症的发病机制中起着明确的作用。我们研究了子宫内膜异位症中的组蛋白乙酰化状态，以及组蛋白去乙酰化酶抑制剂（HDACIs）在子宫内膜异位症治疗中的应用。
评估了子宫内膜异位症囊肿基质细胞（ECSCs）和正常子宫内膜基质细胞（NESCs）中的乙酰化组蛋白水平。研究了 HDACIs 对 ECSCs 和 NESCs 增殖、细胞周期、凋亡的影响，以及与这些细胞事件相关的基因表达。还研究了 HDACIs 对 ECSCs 细胞周期调节基因启动子区染色质组蛋白乙酰化的影响。
ECSCs 中的乙酰化组蛋白水平明显低于 NESCs（P<0.025）。HDACIs 抑制 ECSCs 的增殖，并诱导细胞周期停滞和凋亡。HDACIs 对 NESCs 的作用较小或较弱。这些 HDACIs 导致 ECSCs 中总细胞染色质和 p16(INK4a)、p21(Waf1/Cip1)、p27(Kip1) 和周期检查点激酶 2 基因启动子区的乙酰化组蛋白积累。HDACIs 诱导这些细胞周期调节剂的蛋白表达，并抑制 ECSCs 中 Bcl-2 和 Bcl-X(L)的蛋白表达。
本研究结果表明，子宫内膜异位症中存在异常的组蛋白修饰，HDACIs 重新激活了表观遗传沉默的基因，从而抑制了 ECSCs 的增殖，诱导了细胞周期停滞和凋亡。因此，HDACIs 是治疗子宫内膜异位症的有前途的药物。
