Identification of the E2F1-RAD51AP1 axis as a key factor in MGMT-methylated GBM TMZ resistance

作     者：Junhu Zhou Fei Tong Jixing Zhao Xiaoteng Cui Yunfei Wang Guangxiu Wang Chunsheng Kang Xiaomin Liu Qixue Wang Junhu Zhou;Fei Tong;Jixing Zhao;Xiaoteng Cui;Yunfei Wang;Guangxiu Wang;Chunsheng Kang;Xiaomin Liu;Qixue Wang

作者机构：Tianjin Medical University General HospitalTianjin 300052China Tianjin Neurological InstituteKey Laboratory of NeurotraumaVariationand RegenerationMinistry of Education and Tianjin Municipal GovernmentTianjin 300052China Department of OncologyGamma Knife CenterDepartment of Neurological SurgeryTianjin Huanhu HospitalNankai UniversityTianjin 300350China 

出 版 物：《Cancer Biology & Medicine》 (癌症生物学与医学（英文版）)

年 卷 期：2023年第20卷第5期

页      面：385-400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 the Science and Technology Project of Tianjin Municipal Health Commission(Grant Nos.TJWJ2022MS003 and TJWJ2021ZD008) the Tianjin Science and Technology Plan Project(Grant Nos.21JCYBJC01520 and 20JCYBJC01070) 

主　　题：TMZ EGFRvIII E2F1 RAD51AP1 MGMT 

摘      要：Objective:Epidermal growth factor receptor variant III(EGFRvIII)is a constitutively-activated mutation of EGFR that contributes to the malignant progression of glioblastoma multiforme(GBM).Temozolomide(TMZ)is a standard chemotherapeutic for GBM,but TMZ treatment benefits are compromised by *** study aimed to elucidate the crucial mechanisms leading to EGFRvIII and TMZ ***:CRISPR-Cas13a single-cell RNA-seq was performed to thoroughly mine EGFRvIII function in *** blot,realtime PCR,flow cytometry,and immunofluorescence were used to determine the chemoresistance role of E2F1 and RAD51-associated protein 1(RAD51AP1).Results:Bioinformatic analysis identified E2F1 as the key transcription factor in EGFRvIII-positive living *** RNA-seq analysis revealed that E2F1 is a crucial transcription factor under TMZ *** blot suggested enhanced expression of E2F1 in EGFRvIII-positive and TMZ-treated glioma *** of E2F1 increased sensitivity to *** diagram profiling showed that RAD51AP1 is positively correlated with E2F1,mediates TMZ resistance,and has a potential E2F1 binding site on the *** of RAD51AP1 enhanced the sensitivity of TMZ;however,overexpression of RAD51AP1 was not sufficient to cause chemotherapy resistance in glioma ***,RAD51AP1 did not impact TMZ sensitivity in GBM cells with high O6-methylguanine-DNA methyltransferase(MGMT)*** level of RAD51AP1 expression correlated with the survival rate in MGMT-methylated,but not MGMT-unmethylated TMZ-treated GBM ***:Our results suggest that E2F1 is a key transcription factor in EGFRvIII-positive glioma cells and quickly responds to TMZ ***51AP1 was shown to be upregulated by E2F1 for DNA double strand break *** RAD51AP1 could facilitate achieving an ideal therapeutic effect in MGMT-methylated GBM cells.