Histone demethylase KDM9 activates the CCND1/AKT pathway to promote the malignant progression of gliomas through interaction with BRD2.

Gliomas are highly aggressive brain tumors with limited treatment options, thus, it is necessary to identify new molecular targets for therapeutic intervention. Epigenetic aberration plays a vital role in the malignant progression of tumors. KDM9 is a histone demethylase, but its function and mechanism in tumors remain unclear. In the present study, we found that KDM9 was highly expressed in malignant gliomas and that it promoted the proliferation, invasion, stem-like characteristics, and temozolomide (TMZ) resistance of tumor cells. Mechanistically, KDM9 mediated the demethylation of H4K20me2 on the CCND1 promoter and interacted with the transcription factor BRD2 to facilitate CCND1 transcription, further enhancing the AKT signaling pathway, thereby promoting the malignant progression and TMZ resistance of glioma cells. In vivo experiments also demonstrated that KDM9 knockdown suppressed xenograft growth and TMZ resistance. Our study clarified the role and mechanism of the epigenetic regulatory molecule KDM9 in the malignant progression and drug resistance of gliomas, thus providing a potential predictive and interventional target for glioma. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-025-05900-9.