Department of Gynaecology and Obstetrics, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, Suzhou, P.R. China.
Bioengineered. 2022 May;13(5):12583-12597. doi: 10.1080/21655979.2022.2074620.
Impaired activity of the trophoblasts is a major contributor to the progression of pregnancy pathologies including preeclampsia (PE). This research probed the function of enhancer of zeste homolog 2 (EZH2) in activity of trophoblast cells and its correlation with growth arrest and DNA damage inducible alpha (GADD45A). EZH2 was predicted to be downregulated in placental tissues in PE according to a gene chip analysis, and reduced expression of EZH2 was detected in the placental tissues of patients with PE. Overexpression of EZH2 augmented proliferation and invasiveness of two trophoblast cell lines HTR-8/SVneo and JEG3 cells. EZH2 catalyzed trimethylation of lysine 27 on histone 3 (H3K27me3) in GADD45A promoter to suppress its transcription. GADD45A silencing increased the activity of the trophoblast cell lines and inactivated the p38/mitogen-activated protein kinase (MAPK) signaling pathway. Rescue experiments confirmed that either inhibition of GADD45A or p38 restored the proliferation, migration, and invasiveness of the trophoblast cell lines suppressed by EZH2 silencing. In conclusion, this work suggests that EZH2 enhances activity of trophoblast cell lines by suppressing GADD45A-mediated p38/MAPK signaling pathway.
滋养细胞活性受损是包括子痫前期 (PE) 在内的妊娠病理进展的主要原因。这项研究探讨了增强子结合蛋白 2（EZH2）在滋养细胞活性中的作用及其与生长停滞和 DNA 损伤诱导的 alpha（GADD45A）的相关性。根据基因芯片分析，EZH2 预计在 PE 胎盘组织中下调，PE 患者胎盘组织中检测到 EZH2 表达减少。EZH2 的过表达增强了两种滋养细胞系 HTR-8/SVneo 和 JEG3 细胞的增殖和侵袭能力。EZH2 在 GADD45A 启动子上催化组蛋白 3（H3K27me3）赖氨酸 27 的三甲基化，从而抑制其转录。GADD45A 沉默增加了滋养细胞系的活性并使 p38/丝裂原活化蛋白激酶（MAPK）信号通路失活。挽救实验证实，GADD45A 或 p38 的抑制均可恢复 EZH2 沉默抑制的滋养细胞系的增殖、迁移和侵袭能力。总之，这项工作表明，EZH2 通过抑制 GADD45A 介导的 p38/MAPK 信号通路增强滋养细胞系的活性。
