Histone Demethylase KDM4A Activates ERRγ-Dependent Cell Cycle Progression to Promote Endometrial Cancer Progression

Endometrial cancer is driven by complex genetic and epigenetic alterations, yet the key chromatin-dependent mechanisms sustaining malignant proliferation remain incompletely defined. Here, we report that lysine demethylase 4A (KDM4A) is aberrantly upregulated in endometrial cancer cells and promotes aggressive growth by epigenetically activating estrogen-related receptor γ (ERRγ). Mechanistically, KDM4A binds to the ERRγ promoter and, through its histone demethylase activity, selectively removes the repressive H3K9me3 mark, thereby relieving transcriptional silencing and elevating ERRγ expression. Functionally, ERRγ acts as a downstream transcription factor that enhances the transcription and protein abundance of cell cycle–associated regulators, facilitating the G2-to-M phase transition and accelerating malignant proliferation. Importantly, pharmacological inhibition of KDM4A using JIB-04 markedly suppresses tumor growth both in vitro and in vivo, concomitant with restoration of H3K9me3 enrichment at the ERRγ promoter, downregulation of ERRγ and its cell cycle gene program, and induction of G2/M arrest. Together, our findings establish a KDM4A–H3K9me3–ERRγ signaling cascade that links epigenetic derepression to cell cycle progression in endometrial cancer, and they provide preclinical evidence that targeting KDM4A with JIB-04 represents a promising therapeutic strategy to curb endometrial cancer proliferation.