Histone Deacetylase Sirtuin 2 Enhances Viability of Trophoblasts Through p65-Mediated MicroRNA-146a/ACKR2 Axis

Reduced activity of trophoblast cells is well-recognized to lead to preeclampsia (PE) progression. This study aims to evaluate the roles of histone deacetylase sirtuin 2 (SIRT2) in activity of trophoblast cells and the molecules involved. Differentially expressed genes in placental tissues between PE patients and healthy individuals were screened using microarray analyses. SIRT2 and atypical chemokine receptor 2 (ACKR2) were downregulated while miR-146a was upregulated in PE patients. SIRT2 was localized in placental syncytiotrophoblasts. Upregulation of SIRT2 enhanced viability, migration and invasion, while reduced apoptosis of HTR-8/SVneo cells. SIRT2 was found to trigger p65 deacetylation level and suppress miR-146a expression according to the luciferase and ChIP assays, whereas miR-146a was found to target ACKR2. Downregulation of p65 promoted migration and invasion of cells. Overexpression of miR-146a inhibited cell viability and blocked the function of SIRT2. ACKR2 was downregulated in tissues from PE women and its upregulation blocked the role of miR-146a. To conclude, SIRT2 promotes p65 deacetylation to suppress miR-146a expression and upregulates ACKR2 expression, therefore enhancing proliferation, migration, and invasion of HTR-8/SVneo cells. This study may offer novel thoughts into the management of PE.