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

  • Cell Mol Life Sci. 2025 Nov 26;82(1):423. doi: 10.1007/s00018-025-05900-9.
Jin Cheng  #  1  2 ,  Xingzhi Peng  #  1  2 ,  Siyuan Tang  1 ,  Peijun Zhou  1  2 ,  Zhuan Zhou  2  3 ,  Zenghui Mao  4 ,  Dan Li  5 ,  Lifang Yang  6  7 ,  Jinwu Peng  8  9
Affiliations
  • 1. Department of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410078, China.
  • 2. Cancer Research Institute, Xiangya School of Basic Medicine Science, Central South University, Changsha, 410078, China.
  • 3. Department of Laboratory Medicine, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, China.
  • 4. Hunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, Changsha, 410007, China.
  • 5. Department of Life Science, College of Biology, Hunan University, Changsha, 410012, China.
  • 6. Department of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410078, China. [email protected].
  • 7. Cancer Research Institute, Xiangya School of Basic Medicine Science, Central South University, Changsha, 410078, China. [email protected].
  • 8. Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410078, China. [email protected].
  • 9. Department of Pathology, Xiangya Changde Hospital, Changde, 415000, China. [email protected].
  • # Contributed equally.
PMID: 41291235 DOI: 10.1007/s00018-025-05900-9
Abstract

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.

Keywords
BRD2; CCND1; Glioma; KDM9; TMZ sensitivity.
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