Distinct H3K27 Methylation States Drive Cellular Responses to the Histone Demethylase Inhibitor GSK-J4 in Ovarian...

The deregulation of histone methylation has been implicated in the pathogenesis of multiple diseases, including ovarian cancer, one of the most lethal gynecologic malignancies worldwide. The roles of the lysine 27 on histone 3 (H3K27) demethylases UTX and JMJD3-key regulators of epigenetic homeostasis-remain incompletely characterized in ovarian cancer. In this study, we used the demethylase inhibitor GSK-J4 and siRNA-mediated knockdown of UTX and JMJD3 to investigate the functional impact of altered H3K27 methylation in ovarian cancer in vitro models. Pharmacologic modulation of lysine di- and trimethylation (H3K27me2/3) induced distinct cell type-specific phenotypes, including reduced proliferation, apoptosis, and alterations in 3D spheroid architecture. These effects were accompanied by transcriptional downregulation of epithelial-mesenchymal transition- and extracellular matrix-associated genes. Notably, we identified the androgen receptor (AR) as a key upstream regulator of H3K27 methylation. In AR-expressing ovarian cancer cells, AR inhibition increased H3K27me2/3 levels, revealing a novel epigenetic axis linking nuclear receptor signaling with histone methylation dynamics. Together, our findings uncover context-dependent vulnerabilities in ovarian cancer cells and highlight a potential therapeutic interplay between AR signaling and epigenetic modulation.