Distinct H3K27 methylation states drive cellular responses to the histone demethylase inhibitor GSK-J4 in ovarian cancer cells

Abstract The deregulation of histone methylation has been implicated in the pathogenesis of multiple diseases, including ovarian cancer (OC), one of the most lethal gynaecological malignancies worldwide. The roles of the H3K27 demethylases UTX and JMJD3– key regulators of epigenetic homeostasis– remain incompletely characterised in OC. Here, 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 OC in vitro models. Pharmacological modulation of 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 EMT- and ECM-associated genes. Notably, we identified the androgen receptor (AR) as a key upstream regulator of H3K27 methylation. In AR-expressing OC cells, AR inhibition increased H3K27me2/3 levels, revealing a novel epigenetic axis linking nuclear receptor signalling with histone methylation dynamics. Together, our findings uncover context-dependent vulnerabilities in OC cells and highlight a potential therapeutic interplay between AR signalling and epigenetic modulation.