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Epigenetic silencing L3MBTL4 sensitizes esophageal cancer to DNA-PKcs inhibitor

Yuan Li1,2, Aiai Gao2, Yuanxin Yao2

  • 1Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, Henan, China.

Cancer Biology & Therapy
|March 25, 2026
PubMed
Abstract

Insights

L3MBTL4 acts as a tumor suppressor in esophageal squamous cell carcinoma (ESCC) by inhibiting proliferation and promoting apoptosis. Its methylation indicates sensitivity to DNA-PKcs inhibitors, offering a new therapeutic strategy for ESCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Esophageal squamous cell carcinoma (ESCC) lacks effective treatments for advanced stages.
  • Synthetic lethality offers novel therapeutic strategies for cancers with epigenetic alterations.
  • Identifying molecules in DNA damage repair and cell fate is crucial for cancer therapy.

Purpose of the Study:

  • To investigate the function of L3MBTL4, a novel Malignant Brain Tumor (MBT) domain protein, in ESCC.
  • To explore the therapeutic potential of L3MBTL4 in ESCC based on its role in DNA damage response and cell fate.

Main Methods:

  • Lentiviral infection to re-express L3MBTL4.
  • Immunoprecipitation, immunofluorescence, and comet assays.
  • Homologous recombination (HR) and non-homologous end joining (NHEJ) reporter assays were utilized.

Main Results:

  • L3MBTL4 expression is regulated by promoter methylation.
  • L3MBTL4 suppressed ESCC cell proliferation, induced G1/S arrest and apoptosis, and promoted ATM signaling.
  • L3MBTL4 inhibited NHEJ signaling by interacting with KU70, sensitizing ESCC cells to DNA-PKcs inhibitors.

Conclusions:

  • L3MBTL4 functions as a tumor suppressor in ESCC.
  • Methylation of L3MBTL4 serves as a predictive biomarker for DNA-PKcs inhibitor efficacy in ESCC treatment.
Keywords:
DNA methylationESCCL3MBTL4NU7441synthetic lethality

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