Epigenetic silencing of BEND4, a novel DNA damage repair gene, is a synthetic lethal marker for ATM inhibitor in pancreatic cancer

Abstract

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.

Keywords

BEND4 / DNA methylation / synthetic lethality / NHEJ pathway

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Acknowledgements

We sincerely thank Xiaomo Su for experimental preparation. This work was supported by grants from the National Key Research and Development Program of China (Nos. 2018YFA0208902 and 2020YFC2002705), the National Natural Science Foundation of China (Nos. 82272632 and 81672138), and Beijing Science Foundation of China (No. 7171008).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-1053-3 and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest Yuanxin Yao, Honghui Lv, Meiying Zhang, Yuan Li, James G. Herman, Malcolm V. Brock, Aiai Gao, Qian Wang, Francois Fuks, Lirong Zhang and Mingzhou Guo declare that they have no conflict of interest.

All institutional and national guidelines for the care and use of laboratory animals were followed.

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