Histone demethylase KDM4A promotes endometrial cancer progression through an ERRγ-associated cell-cycle regulatory...

Endometrial cancer (EC) is driven by complex genetic and epigenetic alterations, but the specific chromatin-dependent mechanisms that sustain malignant proliferation remain incompletely understood. In this study, we found that lysine demethylase 4A (KDM4A) was upregulated in EC and promoted cell proliferation, migration, and invasion, accompanied by increased estrogen-related receptor gamma (ERRγ) expression. Mechanistically, KDM4A promoted ERRγ expression in association with reduced enrichment of the repressive H3K9me3 modification at the ESRRG promoter, suggesting that KDM4A may facilitate ESRRG transcription by attenuating H3K9me3-associated repression. Functionally, ERRγ acted as a downstream mediator associated with increased CDK1 transcription and elevated CDK1 and Cyclin B1 protein expression. These findings suggest that the KDM4A-ERRγ axis contributes to G2/M-phase regulation and EC cell proliferation. Importantly, treatment with the KDM4-family inhibitor QC6352 significantly suppressed EC cell growth in vitro and reduced xenograft tumor growth in vivo. These findings support a model in which KDM4A-associated reduction of H3K9me3 enrichment at the ESRRG promoter contributes to ERRγ upregulation and altered cell-cycle regulation in EC cells. Furthermore, these findings provide preliminary preclinical support for further investigation of KDM4-family inhibition as a potential therapeutic approach in EC.