EZH2 Enhances Proliferation and Migration of Trophoblast Cell Lines by Blocking GADD45A-mediated P38/MAPK Signaling Pathway

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.