Abstract
Histone H3 lysine 4 trimethylation (H3K4me3) is one of the most recognized epigenetic regulators of transcriptional activity representing, an epigenetic modification of Histone H3. Previous reports have suggested that the broad H3K4me3 domain can be considered as an epigenetic signature for tumor-suppressor genes in human cells. G-protein-coupled estrogen receptor (GPER), a new membrane-bound estrogen receptor, acts as an inhibitor on cell growth via epigenetic regulation in breast and ovarian cancer cells. This study was conducted to evaluate the relationship of GPER and H3K4me3 in ovarian cancer tissue samples as well as in two different cell lines (Caov3 and Caov4). Silencing of GPER by a specific siRNA and two selective regulators with agonistic (G1) and antagonistic (G15) activity were applied for consecutive in vitro studies to investigate their impacts on tumor cell growth and the changes in phosphorylated ERK1/2 (p-ERK1/2) and H3K4me3. We found a positive correlation between GPER and H3K4me3 expression in ovarian cancer patients. Patients overexpressing GPER as well as H3K4me3 had significantly improved overall survival. Increased H3K4me3 and p-ERK1/2 levels and attenuated cell proliferation and migration were observed in Caov3 and Caov4 cells via activation of GPER by G1. Conversely, antagonizing GPER activity by G15 resulted in opposite effects in the Caov4 cell line. In conclusion, interaction of GPER and H3K4me3 appears to be of prognostic significance for ovarian cancer patients. The results of the in vitro analyses confirm the biological rationale for their interplay and identify GPER agonists, such as G1, as a potential therapeutic approach for future investigations.
Highlights
Introduction conditions of the Creative CommonsEpithelial ovarian cancer (EOC) is the fifth leading cause of female cancer-associated death in Western countries [1]
According to previous studies of G-protein-coupled estrogen receptor (GPER) and H3K4me3 localization, GPER staining was predominantly observed in the cytoplasm and membrane in ovarian cancer specimens, while H3K4me3 staining primarily localized within the nuclei of EOC cells (Figure 1)
Our data suggests that GPER is involved in mediating the epigenetic regulation of H3K4me3 expression in ovarian cancer
Summary
Epithelial ovarian cancer (EOC) is the fifth leading cause of female cancer-associated death in Western countries [1]. Estradiol (E2) is an important determinant of gynecologic malignancies, including ovarian cancer [4,5]. In this context, G-protein-coupled estrogen receptor (GPER) is a new member of the G-protein-coupled receptor (GPCR) family, mediating signals into the cells via its trans-membrane domains [6]. In 2000, a study reported that rapid 17β-estradiolmediated activation of extracellular signal-regulated kinases (ERKs) was dependent on the protein of an orphan G-protein-coupled receptor with seven transmembrane domains [7]
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