Dysregulation of HDAC9 Represses Trophoblast Cell Migration and Invasion Through TIMP3 Activation in Preeclampsia.
Dysregulation of HDAC9 Represses Trophoblast Cell Migration and Invasion Through TIMP3 Activation in Preeclampsia.
复制标题
先兆子痫中 HDAC9 失调通过 TIMP3 激活抑制滋养层细胞迁移和侵袭。
DOI：
10.1093/ajh/hpz006
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发表时间：
2019
影响因子：
3.2
通讯作者：
Li Ting
中科院分区：
文献类型：
--
作者：
Xie D;an;Zhu Jingping;Liu Qianqian;Li Jun;Song Mengjiu;Wang Kai;Zhou Qian;Jia Yuanhui;Li Ting
背景与目的子痫前期(Preeclampsia，PE)是妊娠期的常见病。一般认为，PE与滋养细胞功能障碍引起的浅层胎盘着床密切相关。滋养层细胞与肿瘤细胞具有共同的组织学和行为学特征，许多证据强调组蛋白脱乙酰酶(HDACs)是治疗肿瘤的最有前途的靶点。然而，HDAC在PE中的作用还没有得到很好的确立。本研究旨在研究HDACs在子痫前期胎盘组织中的表达，探讨其在子痫前期发病中的作用。方法采用Q-RT-PCR和免疫印迹方法检测正常胎盘和子痫前期胎盘组织中HDAC9的表达水平。用免疫组织化学方法对HDAC9进行定位。用Transwell法和MTS法分别检测滋养层细胞的迁移和增殖。用染色质免疫沉淀-定量聚合酶链式反应(ChIP-qPCR)方法检测组织金属蛋白酶抑制因子3(TIMP3)启动子的组蛋白乙酰化水平。结果子痫前期胎盘组织中TIMP3启动子的组蛋白乙酰化水平较正常对照组下调，主要定位于合体滋养层细胞的胞核。HDAC9基因敲除HTR-8/SVneo细胞可抑制细胞迁移和侵袭。在HDAC9基因敲除的HTR-8/SVneo细胞中，由于组蛋白高乙酰化，TIMP3的转录水平上调。结论HDAC9通过组蛋白去乙酰化抑制TIMP3，从而促进滋养层细胞的迁移和侵袭。因此，我们的研究结果表明，HDAC9和TIMP3的异常调节与PE有关。
BACKGROUND AND OBJECTIVEPreeclampsia (PE) is a common disease during pregnancy. It is generally accepted that PE is closely associated with shallow placenta implantation caused by the dysfunction of trophoblast cells. Trophoblasts have been recognized to share histological and behavioral characteristics with cancer cells, and many lines of evidence have emphasized that histone deacetylases (HDACs) are therapeutic targets for cancer treatment with the most promising. However, the roles of HDACs have not been well established in PE. The purpose of this study is investigating the expression of HDACs in preeclamptic placentas and to explore its roles in PE progression.METHODSBoth mRNA and protein levels of HDAC9 were determined by q-RT-PCR and western blot in normal and preeclamptic placentas. The localization of HDAC9 was performed by immunohistochemistry. Trophoblast cell mobility and proliferation were determined by transwell and MTS assays, respectively. The histone acetylation levels of the tissue inhibitor of metalloproteinases 3 (TIMP3) promoter were detected by chromatin immunoprecipitation–quantitative polymerase chain reaction (ChIP–qPCR) assay.RESULTSHDAC9 was downregulated in preeclamptic placentas compared with that in normal controls, and it was mainly localized in the nucleus of syncytiotrophoblast cells. HDAC9 knockdown in HTR-8/SVneo cells inhibited cell migration and invasion. The transcriptional level of TIMP3 was upregulated in HDAC9-knockdown HTR-8/SVneo cells because of promoter histone hyperacetylation. Importantly, HDAC9 downregulation can rescue the defects caused by HDAC9 knockdown.CONCLUSIONSHDAC9 promotes trophoblast cell migration and invasion by repressing TIMP3 through promoter histone hypoacetylation. Thus, the findings of our study suggest that dysregulated HDAC9 and TIMP3 are relevant to PE.