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

作　　者：Yuanxin Yao Honghui Lv Meiying Zhang Yuan Li James G.Herman Malcolm V.Brock Aiai Gao Qian Wang Francois Fuks Lirong Zhang Mingzhou Guo 

机构地区：[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

出　　处：《Frontiers of Medicine》2024年第4期721-734,共14页医学前沿（英文版）

基　　金：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);Beijing Science Foundation of China(No.7171008)。

摘　　要：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.

关 键 词：BEND4 DNA methylation synthetic lethality NHEJ pathway 

分 类 号：R73[医药卫生—肿瘤]