Peroxiredoxin2 regulates trophoblast proliferation and migration through SPIB-HDAC2 pathway.
Peroxiredoxin2 regulates trophoblast proliferation and migration through SPIB-HDAC2 pathway.
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DOI：
10.1016/j.yexcr.2022.113428
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发表时间：
2022-11
影响因子：
3.7
通讯作者：
Fan Wu;Fu-Ju Tian;Chuanmei Qin;Xiaoli Qin;Weihong Zeng;Xiaorui Liu;Cailian Chen;Yi Lin
中科院分区：
文献类型：
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作者：
Fan Wu;Fu-Ju Tian;Chuanmei Qin;Xiaoli Qin;Weihong Zeng;Xiaorui Liu;Cailian Chen;Yi Lin
胎盘滋养层细胞的增殖和迁移是妊娠成功的先决条件。Peroxiredoxin 2（Prdx 2）是一个多功能基因，参与各种信号事件，以维持基本的生物学功能和正常的细胞稳态。在这项研究中，在患有复发性流产（RM）的女性的前三个月细胞滋养层中发现了显著较低的Prdx 2水平。prdx 2下调抑制滋养细胞增殖和迁移。我们发现组蛋白脱乙酰酶2（HDAC 2）在Prdx 2下游调节滋养层细胞增殖和迁移。HDAC 2可使E-cadherin（E-cad）启动子中的组蛋白-3-赖氨酸-9去乙酰化，从而降低E-cad的转录，而促进SlugandSnail基因的表达。这些分子变化可能有助于滋养层上皮间质转化。我们进一步验证了Prdx 2是否通过SPIB调节HDAC 2的表达。SPIB可与HDAC 2启动子PU-box区域结合，诱导HDAC 2表达。在RM中，Prdx 2下调抑制SPIB-HDAC 2通路，导致E-cad增加，Slug和Snail减少，并最终抑制滋养层细胞增殖和迁移。我们的研究揭示了Prdx 2调节的SPIB-HDAC 2通路在RM病理学中的作用，并为RM以及其他“重大产科综合征”（包括先兆子痫和宫内生长受限）提供了诊断和治疗靶点。
Adequate proliferation and migration of placental trophoblasts is the prerequisite of a successful pregnancy. Peroxiredoxin2 (Prdx2) is a multi-functional gene involved in various signal events to maintain essential biological functions and normal cellular homeostasis. In this study, substantially lower Prdx2 levels were found in the first trimester cytotrophoblasts of women who suffered from recurrent miscarriage (RM). Prdx2 downregulation inhibited trophoblast proliferation and migration. We demonstrated that histone deacetylase2 (HDAC2) acts downstream of Prdx2 in regulating trophoblast proliferation and migration. HDAC2 deacetylates histone-3-lysine-9 in E-cadherin (E-cad) promoter and reduces the transcription of E-cad epigenetically, whereas it promotes the expression ofSlugandSnailgenes. These molecular changes may contribute to the trophoblast epithelial-mesenchymal transition. We further verified whether Prdx2 modulated the expression of HDAC2 through SPIB. SPIB could bind to the HDAC2 promoter PU-box region and induce HDAC2 expression. In RM, down-regulated Prdx2 suppresses SPIB-HDAC2 pathway, leading to increased E-cad and decreased Slug and Snail, and eventually restrains trophoblast proliferation and migration. Our study unveils the role of Prdx2-regulated SPIB-HDAC2 pathway in the pathology of RM and provides diagnostic and therapeutic targets for RM as well as other “great obstetrical syndromes” including preeclampsia and intrauterine growth restriction.