KAT2B inhibits cholangiocarcinoma proliferation by binding with histone demethylase KDM6B
- Biochim Biophys Acta Mol Basis Dis. 2026 Aug;1872(6):168242. doi: 10.1016/j.bbadis.2026.168242.
- 1. Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China; Department of Radiology, Lishui Central Hospital, The Fifh Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China; Key Laboratory of Precision Medicine of Lishui, Lishui, 323000, China; Clinical College of The Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, China.
- 2. Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China.
- 3. Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China; Department of Radiology, Lishui Central Hospital, The Fifh Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China.
- 4. Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China; Department of Radiology, Lishui Central Hospital, The Fifh Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China; Clinical College of The Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, China.
- 5. Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China; Department of Radiology, Lishui Central Hospital, The Fifh Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China; Key Laboratory of Precision Medicine of Lishui, Lishui, 323000, China; Clinical College of The Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, China. Electronic address: [email protected].
- 6. Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China; Department of Radiology, Lishui Central Hospital, The Fifh Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China; Clinical College of The Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, China. Electronic address: [email protected].
Background: Cholangiocarcinoma is a highly malignant tumor of the biliary system with a poor prognosis. The epigenetic molecular mechanisms underlying its occurrence and progression remain unclear, and no effective molecular targets for clinical treatment have been identified.
Methods: EdU incorporation, colony formation, growth curve, TUNEL, transwell, and wound-healing assays were used to assess the role of KAT2B in cholangiocarcinoma proliferation, metastasis, and Apoptosis. Immunoaffinity purification coupled with mass spectrometry was used to identify KAT2B-interacting proteins, GST pull-down assays were conducted to assess direct interactions between KAT2B and its binding partners, and RNA Sequencing, ChIP, and chromatin-binding assays were performed to investigate the regulatory mechanisms of KAT2B and histone demethylases on target genes. In vivo experiments further validated KAT2B's role in cholangiocarcinoma proliferation and metastasis.
Results: KAT2B is significantly downregulated in cholangiocarcinoma. Both in vitro and in vivo experiments demonstrated that KAT2B significantly inhibits cholangiocarcinoma cell proliferation and metastatic potential. Mass spectrometry revealed that KAT2B interacts with Histone Demethylase KDM6B, forming a KAT2B/KDM6B complex that regulates the downstream target genes PTPN12 and CDKN1A. Disruption of any component of this complex leads to reduced chromatin binding and occupancy of the PTPN12 and CDKN1A promoter region by the remaining components. The increased proliferation induced by KAT2B interference can be rescued by PTPN12 overexpression, and changes in proliferation phenotype caused by KAT2B are dependent on its enzymatic activity.
Conclusions: KAT2B acts as a tumor suppressor by promoting PTPN12 expression through its interaction with KDM6B, thereby inhibiting cholangiocarcinoma proliferation.