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 

作者机构：Department of Gastroenterology and Hepatologythe First Medical CenterChinese PLA General HospitalBeijing100853China Department of PharmacologySchool of Basic Medical SciencesZhengzhou UniversityZhengzhou450001China Henan Institute of Advanced TechnologyZhengzhou UniversityZhengzhou450001China UPMC Hillman Cancer CenterUniversity of Pittsburgh Medical CenterPittsburghPA15213USA Department of surgerySchool of MedicineJohns Hopkins School of MedicineBaltimoreMD21287USA Laboratory of Cancer EpigeneticsFaculty of MedicineULB-Cancer Research Center(U-CRC)Universite Libre de Bruxelles(ULB)Brussels1070Belgium National Key Laboratory of Kidney Diseasesthe First Medical CenterChinese PLA General HospitalBeijing100853China 

出 版 物：《Frontiers of Medicine》 (医学前沿（英文版）)

年 卷 期：2024年第18卷第4期

页      面：721-734页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

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) 

主　　题：BEND4 DNA methylation synthetic lethality NHEJ pathway 

摘      要：Synthetic lethality is a novel model for cancer *** 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 ***-specific polymerase chain reaction,CRISPR/Cas9,immunoprecipitation assay,comet assay,and xenograft mouse model were ***4 is a new member of the BEN domain *** expression of BEND4 is regulated by promoter region *** 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 ***4 methylation is significantly associated with late-onset PDAC(50 years,P0.01)and tumor differentiation(P0.0001),and methylation of BEND4 is an independent poor prognostic marker(P0.01)in ***,BEND4 plays tumor-suppressive roles in vitro and in ***,BEND4 involves non-homologous end joining signaling by interacting with Ku80 and promotes DNA damage *** of BEND4 increased the sensitivity of PDAC cells to ATM ***,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.