HDAC4 regulates the proliferation, migration, and invasion of trophoblasts in pre‐eclampsia through the miR‐134‐5p/FOXM1 axis

Abstract

Epigenetics, including histone modifications and noncoding RNAs, affects abnormal placental function in pre‐eclampsia (PE). This study was conducted to explore the role of histone deacetylase 4 (HDAC4) in trophoblast invasion and migration. The expression levels of HDAC4, microRNA (miR)‐134‐5p, and forkhead box protein M1 (FOXM1) in placentas from PE patients and healthy controls and their correlations were examined. HTR8/SVneo cells were cultured and underwent gene intervention. Then, trophoblast proliferation, invasion, and migration were evaluated by 5‐ethynyl‐2ʹdeoxyuridine, Transwell, and scratch assays. The enrichments of HDAC4 and acetylated histone H3 at lysine 9 (H3K9Ac) on the miR‐134‐5p promoter were quantified by chromatin immunoprecipitation. The binding of miR‐134‐5p to FOXM1 was analyzed by dual‐luciferase assay. HDAC4 and FOXM1 were downregulated while miR‐134‐5p was upregulated in PE placentas. HDAC4 downregulation impaired trophoblast proliferation, invasion, and migration while HDAC4 overexpression played the opposite role. Mechanically, HDAC4 deacetylated H3K9Ac to repress miR‐134‐5p expression by erasing H3K9Ac, reduced the binding of miR‐134‐5p to FOXM1, and then promoted FOXM1 transcription. miR‐134‐5p overexpression or FOXM1 downregulation abrogated the promotive role of HDAC overexpression in trophoblast invasion and migration. Our study unraveled a novel mechanism of trophoblast proliferation, invasion, and migration and proposed that HDAC4 may be a promising target for the treatment of PE.