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.