KDM4A-mediated histone demethylation of SLC7A11 inhibits cell ferroptosis in osteosarcoma.

Abstract Osteosarcoma (OS) is the most common type of bone tumor that seriously affects limb function and induces great pain in patients. Lung metastasis and chemotherapy resistance are two key issues leading to the poor prognosis of OS patients, therefore new treatment targets and strategies are urgently needed. In our study, we uncovered the role of histone demethylase KDM4A in regulating OS cell ferroptosis and tumor progression. KDM4A was significantly upregulated in OS specimens and high KDM4A expression was associated with poorer prognosis in OS patients. Our data indicated that targeting KDM4A significantly increased OS cell death, enhanced cisplatin response, and attenuated migration ability in vitro. KDM4A depletion dramatically inhibited tumor progression and lung metastasis of OS in vivo Further experiments confirmed that KDM4A knockdown promoted OS cell ferroptosis, a special non-apoptotic form of cell death. KDM4A regulates SLC7A11 transcription and OS cell ferroptosis by controlling H3K9me3 demethylation in the promoter region of SLC7A11. Our findings deepened the recognition of epigenetic regulatory mechanism in OS tumorigenesis, chemoresistance, and metastasis, suggesting that KDM4A activity may be a potential therapeutic target for future OS treatment.