Functional analysis of glycodelin induced by HDACI in endometrial glandular epithelium.

人的子宫内膜在月经期重复增殖、分化(蜕膜化)和组织分解。组蛋白可逆乙酰化由组蛋白乙酰化酶和去乙酰化酶调控，控制基因转录。为了开发治疗着床障碍的新策略，我们分析了组蛋白脱乙酰酶抑制剂(HDACi)替代卵巢类固醇激素作为人子宫内膜分化诱导剂的可能性，并分析了卵巢类固醇激素或HDACi对人子宫内膜腺癌细胞株Ishikawa细胞的影响。与卵巢类固醇激素类似，HDACi影响Ishikawa细胞的下列功能：1)HDACi通过糖蛋白启动子区域诱导分化(黄体期)子宫内膜腺高表达糖蛋白的mRNA和蛋白表达。2)HDACi显示细胞扁平化和广泛性的形态变化。3)HDACi促进糖原的产生。4)HDACi上调单个细胞的运动，跨孔细胞迁移分析。5)HDACi增强细胞的集体运动，6)Glycodelin永久表达克隆显示加速了单个和集体细胞的迁移。7)通过siRNA沉默Glycodelin基因可以消除上述HDACi的影响。综上所述，HDACi可能通过上调糖蛋白的表达来诱导子宫内膜细胞的分化和迁移，为通过靶向糖蛋白调节子宫内膜功能的可能治疗策略提供了线索。

Human uterine endometrium repeats proliferation, differentiation (decidualization) and tissue breakdown during the menstrual period. Histone reversible acetylation, regulated by histone acetylase and deacetylase, govern gene transcription. To develop new strategy of treatment for impairment of implantation, we analyze the possibility of histone deacetylase inhibitors (HDACI) as a differentiation inducer of human endometrium, instead of ovarian steroid hormones.We analyzed the effect of ovarian steroid hormones or HDACI onto Ishikawa cells (human adenocarcinoma cell line), which is used as a model of human endometrial glandular epithelium. In a similar way to ovarian steroid hormones, HDACI affected the following function in Ishikawa cells.1)HDACI induced the both mRNA and protein expression of glycodelin, which is highly expressed in differentiated (luteal-phase) endometrial gland, via glycodelin promoter region.2)Flattened and wide-spread morphological changes of cells were shown by HDACI.3)HDACI enhanced the production of glycogen.4)HDACI up-regulated single cell motility, analyzed with trans-well cell migration assay.5)HDACI enhanced collective cell motility, tested with wound healing assay.6)Glycodelin permanent expression clones showed accelerated single and collective cell migration.7)Glycodelin gene silencing by siRNA abolished the effect by HDACI, mentioned above.Taken together, HDACI have a potential to induce both differentiation and migration of endometrial cells through up-regulation of glycodelin, providing a clue for a possible therapeutic strategy to modulate endometrial function by targeting glycodelin.