L3MBTL4 methylation is a sensitive marker of DNA-PK inhibitor in pancreatic cancer

Aim: The purpose is to explore the mechanism and new therapeutic strategy of lethal 3 malignant brain tumor like 4 (L3MBTL4) gene in pancreatic ductal adenocarcinoma (PDAC). Methods: Immunoprecipitation, siRNA knockdown, immunohistochemistry, homologous recombination (HR) and non-homologous end joining (NHEJ) reporter assays, comet assays, and a xenograft mouse model were employed. Results: L3MBTL4 was methylated in 16.3% (7/43) of intraductal papillary mucinous neoplasms, 19.0% (4/21) of mucinous cystic neoplasm, and 28.2% (84/298) of PDAC, and its expression was regulated by promoter region methylation. L3MBTL4 methylation was significantly associated with tumor differentiation and tumor size. The expression of L3MBTL4 inhibited cell proliferation, colony formation, and induced apoptosis and G1/S phase arrest. L3MBTL4 activated ATM/CHK2 and inhibited NHEJ signaling by interacting with Ku70. Loss of L3MBTL4 increased the sensitivity of PDAC cells to NU7441 both in vitro and in vivo. Conclusions: L3MBTL4 is a new component of NHEJ signaling and epigenetic silencing of L3MBTL4 sensitizes PDAC cells to DNA-PK inhibitors, providing a potential new therapeutic strategy.