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    • Histone modification is one of

    2022-06-22

    Histone modification is one of the major epigenetic mechanisms.8, 10 Specific histone modifications confer active or repressive transcriptional states. For instance, the trimethylation of Histone3-Lysine27 (H3K27me3) is a marker of tightly packaged heterochromatin and is associated with gene repression. Together with DNA hypermethylation, transcriptional factors, and other regulatory subunits, H3K27me3 typically forms complexes to control target gene expressions. In human placental villi, most of the EVTs are H3K27me3-positive when stained by immunohistochemistry. Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2, mediates the transcriptional silencing of target genes through H3K27me3. EZH2 overexpression is associated with aggressiveness and advanced diseases in some cancers.13, 14, 15, 16 Additionally, EZH2 has extensive roles in reproduction. It is a driver of epithelial-mesenchymal transition (EMT) in endometriosis, which impairs fertility. EZH2 is also essential for the early embryogenesis of mice. EZH2-deficient embryos display impaired growth potential and embryonic lethality in mice. However, the functions and mechanisms of EZH2 in human trophoblasts remain unknown. Caudal-related homeobox transcription factor 1 (CDX1) plays essential roles in anteroposterior vertebral patterning and intestinal homeostasis. Increasing evidence demonstrates that CDX1 and CDX2 function as tumor suppressors.21, 22 In addition, the CpG islands of the CDX1 promoter showed abnormal DNA methylation levels in pre-eclampsia patients compared with those from healthy cases. Moreover, CDX1 restricts the invasion of HTR-8/SVneo trophoblast AM095 australia by inhibiting MMP-9 expression. However, the relationship between CDX1 and RM, as well as the upstream epigenetic regulation of CDX1, has not been sufficiently addressed. In this study, we demonstrate that the expression of EZH2 was reduced in the villi of patients with RM, and its downregulation affected trophoblast invasion by inhibiting EMT via epigenetically repressing CDX1. We also found that progesterone (P4) leads to the upregulation of EZH2 through the extracellular signaling-regulated kinase (ERK1/2) pathway in trophoblasts.
    Results
    Discussion The resemblance in the invasive behavior between placental trophoblasts and cancer cells and the role of aberrant epigenetic regulation in cancer development are well-known. Delicate control of trophoblast invasion is important for implantation, uterine spiral artery remodeling, and maternal-fetal communication. Moreover, numerous studies have established a strong link between epigenetic regulation and placental trophoblast function by demonstrating the critical role of epigenetic regulators in maintaining a healthy pregnancy.8, 35, 36 In this study, we investigated the role of EZH2 in the invasiveness of trophoblast. Our data showed that the expression of EZH2 both at mRNA and protein levels was significantly decreased in the villi of women who suffered from RM compared with those from normal pregnant women. The ChIP and dual-luciferase report assays showed that EZH2 could inhibit CDX1 transcription directly through trimethylation of H3K27 at the promoter of CDX1, which inhibited EMT in trophoblast. Thus, EZH2 could indirectly promote trophoblast EMT via CDX1. Moreover, we found that progesterone, which is used to treat or prevent early miscarriages and RM upregulated EZH2 expression via the ERK1/2 signaling pathway, which means the epigenetic mechanisms in the pathogenesis of RM have long been targeted for its therapy to reverse this disadvantage. It is now well established that impaired trophoblast invasion is implicated in the etiology of pregnancy complications, including RM. In our present study, trophoblast invasion was attenuated by silencing of EZH2 or inhibiting of EZH2 enzyme activity with inhibitors. EZH2 overexpression also promoted invasion of trophoblasts. EZH2 can promote the invasion of malignant cancer cells by silencing target genes that are tumor suppressors.37, 38, 39, 40, 41 Among these genes, CDH1 (the gene that encodes E-cadherin) is putatively one of the targets.14, 24 EZH2 facilitates tumor metastasis by directly repressing CDH1 transcription via methylating Histone3-Lysine 27 at the promoter region mainly through E-box regions. E-cadherin is a marker of epithelial cells and is of crucial importance in cancer invasion and metastasis. EMT, featured by reduced E-cadherin and increased N-cadherin expression, has been identified as a characteristic of aggressive tumors; it entitles cells to migratory and invasive capability in carcinogenesis.42, 43 Previous studies have shown that EZH2 physically associates with CDH1 and inhibits E-cadherin transcription via H3K27me3.14, 44 In this study, EZH2 also repressed E-cadherin transcription and protein expression, which was accompanied by the upregulation of N-cadherin and proved that EZH2 directly promoted EMT.