Epigenetic silencing L3MBTL4 sensitizes esophageal cancer to DNA-PKcs inhibitor
- Cancer Biol Ther. 2026 Dec 31;27(1):2646393. doi: 10.1080/15384047.2026.2646393.
- 1. Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, Henan, China.
- 2. Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China.
- 3. Department of Gastroenterology and Hepatology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
- 4. Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
- 5. National Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China.
Background: Esophageal squamous cell carcinoma (ESCC) remains a deadly disease, with no effective therapeutics available for advanced stages. The application of the "synthetic lethality" principle to cancers with abnormal epigenetic changes provides more opportunities for developing novel therapeutic strategies. It is necessary to identify more molecules that are involved in the DNA damage repair response or cell fate determination to reach this end. Malignant brain tumor (MBT) domain proteins are important for development and cell fate. L3MBTL4 is a new member of this family, but its function remains to be clarified.
Methods: Lentiviral Infection was used to re-express L3MBTL4. Immunoprecipitation, immunofluorescence, comet, homologous recombination (HR), and non-homologous end joining (NHEJ) reporter assays were performed to explore the mechanism involved.
Results: The expression of L3MBTL4 was regulated by methylation of the promoter region. L3MBTL4 inhibited cell proliferation and colony formation, and induced G1/S arrest and Apoptosis in ESCC cells. L3MBTL4 promoted ATM signaling and inhibited NHEJ signaling by interacting with KU70. Epigenetic silencing of L3MBTL4 sensitized ESCC cells to NU7441, a DNA-PKcs inhibitor, both in vitro and in vivo.
Conclusion: L3MBTL4 is a potential tumor suppressor and methylation of L3MBTL4 is a sensitive marker of DNA-PKcs inhibitors.