Histone deacetylase inhibitors stimulate cell migration in human endometrial adenocarcinoma cells through up-regulation of glycodelin
Histone deacetylase inhibitors stimulate cell migration in human endometrial adenocarcinoma cells through up-regulation of glycodelin
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DOI：
10.1210/en.2006-0896
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发表时间：
2007-02-01
期刊：
影响因子：
4.8
通讯作者：
Yoshimura, Yasunori
中科院分区：
文献类型：
--
作者：
Uchida, Hiroshi;Maruyama, Tetsuo;Yoshimura, Yasunori
组蛋白去乙酰化酶抑制剂（HDACIs）是近年来发现的一种诱导细胞周期阻滞、细胞分化和凋亡的新型抗癌药物。然而，这表明HDACIs促进细胞迁移和侵袭取决于细胞类型。我们以前曾报道过HDACIs，包括阿司他丁A和辛二酰苯胺异羟肟酸（SAHA）或孕酮与雌激素联合治疗，可以通过上调glycodelin（一种甾体酮诱导的子宫内膜糖蛋白）诱导子宫内膜腺癌石川细胞的细胞分化。鉴于glycodelin在细胞运动中的作用和HDACIs的迁移调节潜力，我们使用伤口愈合试验和transwell迁移试验研究了卵巢类固醇激素、阿司他丁A或SAHA是否影响子宫内膜癌细胞系石川和RL 95 -2的细胞迁移。用卵巢类固醇激素、前列腺素A和SAHA治疗增强了细胞迁移以及glycodelin的上调。SAHA增强的细胞迁移几乎完全被glycodelin的基因沉默所阻断。此外，gycodelin单独过表达导致石川细胞运动性增加。我们的研究结果共同表明，glycodelin积极调节细胞运动作为HDACI增强子宫内膜细胞迁移的介质，这表明glycodelin在月经周期中的动态子宫内膜腺体形态发生的参与。我们的研究结果提出了一种可能性，即HDACIs在治疗glycodelin诱导的子宫内膜癌和其他妇科癌症中的使用可能会增强HDACIs未能发挥分化诱导和/或抗增殖作用的情况下的侵袭。
Histone deacetylase inhibitors (HDACIs) have recently emerged as promising anticancer drugs to induce cell cycle arrest, cytodifferentiation, and apoptosis. It is suggested, however, that HDACIs promote cell migration and invasion depending on the cell type. We have reported previously that treatment with HDACIs, including trichostatin A and suberoylanilide hydroxamic acid (SAHA) or progesterone in combination with estrogen, can induce cytodifferentiation of endometrial adenocarcinoma Ishikawa cells through up-regulation of glycodelin, a progesterone-induced endometrial glycoprotein. Given the reported role of glycodelin in cell motility and the migration-modulating potential of HDACIs, we investigated using wound healing assay and transwell migration assay whether ovarian steroid hormones, trichostatin A, or SAHA affects cell migration in endometrial cancer cell lines, Ishikawa and RL95-2. Treatment with ovarian steroid hormones, trichostatin A, and SAHA enhanced cell migration together with up-regulation of glycodelin. SAHA-augmented cell migration was almost completely blocked by gene silencing of glycodelin. Furthermore, overexpression of gycodelin alone resulted in increased cell motility in Ishikawa cells. Our results collectively indicate that glycodelin positively regulates cell motility acting as a mediator of HDACI-enhanced endometrial cell migration, suggesting the involvement of glycodelin in the dynamic endometrial gland morphogenesis during menstrual cycle. Our results raise a possibility that the use of HDACIs in the therapy for glycodelin-inducible endometrial and presumably other gynecological cancers may enhance invasion in cases in which the HDACIs fail to exert differentiation-inducing and/or antiproliferative effects.