Epigenetic silencing of BEND4, a novel DNA damage repair gene, is a synthetic lethal marker for ATM inhibitor in pancreatic cancer
Yuanxin Yao1, Honghui Lv2,1, Meiying Zhang1, Yuan Li3,1, James G. Herman4, Malcolm V. Brock5, Aiai Gao1, Qian Wang1, Francois Fuks6, Lirong Zhang2(), Mingzhou Guo1,7()
1. Department of Gastroenterology and Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing 100853, China 2. Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China 3. Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001, China 4. UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA 5. Department of surgery, School of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA 6. Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Universite Libre de Bruxelles (ULB), Brussels 1070, Belgium 7. National Key Laboratory of Kidney Diseases, the First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
Synthetic lethality is a novel model for cancer therapy. To understand the function and mechanism of BEN domain-containing protein 4 (BEND4) in pancreatic cancer, eight cell lines and a total of 492 cases of pancreatic neoplasia samples were included in this study. Methylation-specific polymerase chain reaction, CRISPR/Cas9, immunoprecipitation assay, comet assay, and xenograft mouse model were used. BEND4 is a new member of the BEN domain family. The expression of BEND4 is regulated by promoter region methylation. It is methylated in 58.1% (176/303) of pancreatic ductal adenocarcinoma (PDAC), 33.3% (14/42) of intraductal papillary mucinous neoplasm, 31.0% (13/42) of pancreatic neuroendocrine tumor, 14.3% (3/21) of mucinous cystic neoplasm, 4.3% (2/47) of solid pseudopapillary neoplasm, and 2.7% (1/37) of serous cystic neoplasm. BEND4 methylation is significantly associated with late-onset PDAC (> 50 years, P < 0.01) and tumor differentiation (P < 0.0001), and methylation of BEND4 is an independent poor prognostic marker (P < 0.01) in PDAC. Furthermore, BEND4 plays tumor-suppressive roles in vitro and in vivo. Mechanistically, BEND4 involves non-homologous end joining signaling by interacting with Ku80 and promotes DNA damage repair. Loss of BEND4 increased the sensitivity of PDAC cells to ATM inhibitor. Collectively, the present study revealed an uncharacterized tumor suppressor BEND4 and indicated that methylation of BEND4 may serve as a potential synthetic lethal marker for ATM inhibitor in PDAC treatment.
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