Dysregulation of HDAC9 Represses Trophoblast Cell Migration and Invasion Through TIMP3 Activation in Preeclampsia

Abstract

BACKGROUND AND OBJECTIVE Preeclampsia (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. METHODS Both 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. RESULTS HDAC9 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. CONCLUSIONS HDAC9 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.

The Role of Epigenetics in Placental Development and the Etiology of Preeclampsia

“…Knock-down of HDAC9 in HTR-8/SVneo cells inhibits trophoblast cell migration and invasion. TIMP3, an inhibitory of MMP involved in invasion and tissue remodeling, is a direct target of HDAC9, identified by ChIP and is upregulated in the absence of HDAC9 [320].…”

Placental Syncytiotrophoblast-Derived Extracellular Vesicles Carry Active NEP (Neprilysin) and Are Increased in Preeclampsia

“…These authors reported an increase in cardiac NEP as a result of this. Interestingly, histone deacetylation is reported to play a role in preeclampsia by altering trophoblast cell migration [27]. It is possible that such histone deacetylation might regulate placental NEP but further work is required to elucidate this.…”

The role of epigenetic changes in preeclampsia

“…Studies demonstrated that TIMP3 has high expression in PE placentas . HDAC by changing promoter histone acetylation can regulate TIMP3 expression, so plays a necessary role in trophoblast invasion and migration . Xie et al proved that HDAC9 knockdown resulted in the elevated histone acetylation levels of TIMP3 promoter.…”

“…HDAC by changing promoter histone acetylation can regulate TIMP3 expression, so plays a necessary role in trophoblast invasion and migration . Xie et al proved that HDAC9 knockdown resulted in the elevated histone acetylation levels of TIMP3 promoter. VHL tumor suppressor protein is necessary required for proper placental progression and previous studies also proven that Vhl − / − mouse shows failure of placental vasculogenesis .…”