At the maternal-fetal interface, normal proliferation, migration, and invasion of trophoblast cells is essential for maintaining pregnancy [1]. After implantation, the cytotrophoblast cells (CTBs) undergo proliferation and differentiate into either villous or extravillous trophoblast cells. The fusion of the CTBs results in syncytiotrophoblasts (STBs) formation, which serve as a barrier to mediates gas and nutrient exchange between the mother and fetus. The CTBs that proliferate and differentiate into extravillous trophoblasts (EVTs) invade the maternal decidua and remodel maternal spiral vessels to establish the uteroplacental circulation [2,3]. Defective trophoblast development results in deficient maternal spiral artery transformation that gives rise to higher resistance blood supply and reduced perfusion into the intervillous space, leading to damaged villous architecture and impaired placental function [4]. These pathological changes are associated with the “great obstetrical syndromes,” which is a collective term for several pregnancy-related complications including recurrent miscarriage (RM), preeclampsia (PE), intrauterine growth restriction (IUGR), and preterm delivery. The “great obstetrical syndromes” affect more than 15% of pregnancies and have detrimental effects on maternal and fetal mortality and disability rates, as well as their long-term health conditions [4,5]. We previously showed contribution of insufficient trophoblast proliferation, migration, and invasion to the pathogenesis of unexplained RM [[6], [7], [8]]. RM is widely defined as two or more consecutive pregnancy losses before 24 weeks of gestation. It is estimated to affect 1–5% of couples. The proposed causes of RM include genetic, anatomical, and immunological factors, thrombophilia, infection, and endocrinological disorders [9]. However, in up to 50–75% of RM cases, the cause remains unknown [10]. Other evidence has also proved that the etiology and pathogenesis of PE and IUGR are also related with inadequate trophoblast proliferation, migration, and invasion [[11], [12], [13]].

The process of trophoblast migration and invasion is accompanied by cytoskeleton reorganization and loss of cellular polarity and connection. In the first trimester placental development, coherently layered CTBs lose their epithelial phenotype and acquire the mesenchymal characteristics of enhanced motility and invasiveness to differentiate into the invasive EVTs [14]. This developmental process falls under the category of epithelial-mesenchymal transition (EMT) [14]. When EMT happens, the expression of adhesive junction protein E-cadherin (E-cad) decreases. E-cad has been verified to reduce trophoblast cell migration and invasion, and increased levels of E-cad have been detected in the CTBs of RM and PE [6,15]. Meanwhile, molecules that promote EMT, such as Snail, Slug, ZEB1/2, and Twist1/2, are upregulated. Snail and Slug are known to transcriptionally repress E-cad expression, facilitating EMT initiation and progression [16].

Peroxiredoxin2 (Prdx2), belonging to the family of antioxidant Peroxiredoxins, is a typical 2-Cys thioredoxin peroxidase that plays an important role in peroxide scavenging and protecting cell against oxidative stress [17]. Prdx2 is proven to transmit hydrogen peroxide-mediated signaling events in the NF-κB, STAT3, Wnt/β-catenin, and MAPK kinase signaling pathways, which are closely associated with cell proliferation, migration, and invasion [18]. Prdx2 is reportedly overexpressed in various types of cancer cells and tumor tissues. Previously, we have demonstrated that Prdx2 expression decreases in first-trimester villous CTBs of women who suffer from RM. Prdx2 is regulated by c-Myc and decreased Prdx2 contributes to increased apoptosis and restrained proliferation in trophoblast cells through the ROS-related phosphorylated p53 and p38-MAPK/p21 pathways. Our findings indicate that Prdx2 may play an important role in the regulation of trophoblast proliferation and apoptosis during early pregnancy [19]. In this study, we further explore the molecular mechanism of Prdx2 in the regulation of trophoblast proliferation and migration.

Recently, several researchers have paid attention to the role of epigenetics in the development of pregnancy-related diseases. Epigenetics is defined as heritable traits in gene activity that do not come from changes in the sequence of nucleotides in DNA [20]. These epigenetic changes mainly derive from DNA methylation, histone modification, nucleosome remodeling, and posttranscriptional mechanisms such as microRNA [20]. The fundamental unit of chromatin is the nucleosome, in which approximately 165 base pairs of DNA are coiled around an octamer of core histones formed by two copies of histones H2A, H2B, H3 and H4 [20]. Particular amino acid residues of histone N-terminal tails exposed on the nucleosome surface are easy to chemically modify, and these changes include acetylation of lysines, phosphorylation of serines, and methylation of lysines and arginines [21]. These histone modifications are associated with nucleosome assembly and unwinding, leading to different gene transcription. The distinctive roles of histone modifications in gene regulation are also known as “histone code” [21].

The level of acetylation of selected lysine residues of core histones is a reversible modification controlled by the antagonistic activities of histone acetyltransferases (HATs) and deacetylases (HDACs) [21]. HDACs are catalyzing enzymes that remove histone-tail acetyl groups. Increased levels of histone acetylation loosen the structure of nucleosomes and increase the accessibility of DNA for replication and transcription, whereas decreased levels of acetylation are correlated with gene suppression [21,22]. Moreover, acetylation at different positions is likely to function differently [22]. HDACs are widely expressed in nearly all types of tissues and cells, and abnormal activities of HDACs can lead to disease states. Increased HDACs are discovered in various kinds of cancer cells and proven to promote cell migration and metastasis [[23], [24], [25]]. HDAC inhibitors such as Trichostatin A can inhibit the action of HDAC2 and increase histone acetylation. According to research, HDAC inhibitors have the ability to repress cancer initiation and progression by restarting the expression of tumor suppression genes, activating cell cycle arrest, inducing cell apoptosis, and inhibiting angiogenesis [26]. HDAC inhibitors are now emerging as potential anticancer agents [27].

In this study, our results unveil a Prdx2-mediated SPIB-HDAC2 pathway in the regulation of trophoblast cell proliferation and migration. Abnormal expression of these molecules may be related with the pathology of RM, as well as other “great obstetrical syndromes”, which may provide a potent diagnostic and therapeutic approach for pregnancy-related complications.