Epigenetic silencing schlafen-11 sensitizes esophageal cancer to ATM inhibitor  

作　　者：Jing Zhou Mei-Ying Zhang Ai-Ai Gao Cheng Zhu Tao He James G Herman Ming-Zhou Guo 

机构地区：[1]School of Medicine,NanKai University,Tianjin 300071,China [2]Department of Gastroenterology and Hepatology,The First Medical Center,Chinese PLA General Hospital,Beijing 100853,China [3]Departments of Pathology,Characteristic Medical Center of The Chinese People’s Armed Police Force,Tianjin 300162,China [4]The Hillman Cancer Center,University of Pittsburgh Cancer Institute,Pittsburgh,PA 15213,United States [5]National Key Laboratory of Kidney Diseases,Chinese PLA General Hospital,Beijing 100853,China

出　　处：《World Journal of Gastrointestinal Oncology》2024年第5期2060-2073,共14页世界胃肠肿瘤学杂志（英文版）（电子版）

基　　金：Supported by the National Key Research and Development Program of China,No.2018YFA0208902;National Science Foundation of China,No.82272632,No.81672318,and No.U1604281;Beijing Science Foundation of China,No.7171008;Youth Innovation Science Foundation of Chinese PLA General Hospital,No.22QNCZ027.

摘　　要：BACKGROUND Targeting DNA damage response(DDR)pathway is a cutting-edge strategy.It has been reported that Schlafen-11(SLFN11)contributes to increase chemosensitivity by participating in DDR.However,the detailed mechanism is unclear.AIM To investigate the role of SLFN11 in DDR and the application of synthetic lethal in esophageal cancer with SLFN11 defects.METHODS To reach the purpose,eight esophageal squamous carcinoma cell lines,142 esophageal dysplasia(ED)and 1007 primary esophageal squamous cell carcinoma(ESCC)samples and various techniques were utilized,including methylationspecific polymerase chain reaction,CRISPR/Cas9 technique,Western blot,colony formation assay,and xenograft mouse model.RESULTS Methylation of SLFN11 was exhibited in 9.15%of(13/142)ED and 25.62%of primary(258/1007)ESCC cases,and its expression was regulated by promoter region methylation.SLFN11 methylation was significantly associated with tumor differentiation and tumor size(both P<0.05).However,no significant associations were observed between promoter region methylation and age,gender,smoking,alcohol consumption,TNM stage,or lymph node metastasis.Utilizing DNA damaged model induced by low dose cisplatin,SLFN11 was found to activate non-homologous end-joining and ATR/CHK1 signaling pathways,while inhibiting the ATM/CHK2 signaling pathway.Epigenetic silencing of SLFN11 was found to sensitize the ESCC cells to ATM inhibitor(AZD0156),both in vitro and in vivo.CONCLUSION SLFN11 is frequently methylated in human ESCC.Methylation of SLFN11 is sensitive marker of ATM inhibitor in ESCC.

关 键 词：Schlafen-11 Esophageal squamous cell carcinoma DNA methylation Synthetic lethality AZD0156 

分 类 号：R735.2[医药卫生—肿瘤]