Inmaculada Rioja

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.

SiRNA-mediated knockdown in SKOV3 cells

ARV-110 and enzalutamide modulate H3K27 methylation in CAOV3 and SKOV3 cells

GSK-J4 treatment and gene expression analyses in ovarian cancer cell lines

Morphometric and mechanical profiling of OVCAR-3 and SKOV3 spheroids following GSK-J4 treatment

Si-RNA mediated KDM knockdown in OVCAR-3 cells

SiRNA-mediated knockdown in CAOV3 cells

Effect of GSK-J4 treatment on the H3K27 methylation status of OVCAR-3 and CAOV3 cells

List of the siRNAs used to target KDM6A/UTX and KDM6B/JMJD3

Summary of chromatin regions significantly opened in OVCAR-3 cells following GSK-J4 or ARV-110 treatment