N^(6)-methyladenosine modification of CENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance

作     者：Xian Lin Feng Wang Jian Chen Jing Liu Yi-Bin Lin Li Li Chuan-Ben Chen Qin Xu Xian Lin;Feng Wang;Jian Chen;Jing Liu;Yi?Bin Lin;Li Li;Chuan?Ben Chen;Qin Xu

作者机构：Departments of GynecologyFujian Cancer Hospital and Fujian Medical University Cancer HospitalFujian Medical UniversityFuzhou 350014China Department of Radiation OncologyFujian Cancer Hospital and Fujian Medical University Cancer HospitalFujian Medical UniversityFuzhou 350014China Shenzhen Key Laboratory of Immunity and Inflammatory DiseasesPeking University Shenzhen HospitalShenzhen Peking University?the Hong Kong University of Science and Technology Medical CenterShenzhen 518036GuangdongChina Outpatient DepartmentFujian Hospital of People's Armed PoliceFujian Medical UniversityFuzhou 350014China 

出 版 物：《Military Medical Research》 (军事医学研究（英文版）)

年 卷 期：2022年第9卷第5期

页      面：576-591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：the Joint Funds for the Innovation of Science and Technology Program of Fujian Province,China(2018Y9110) the Natural Science Foundation of Fujian Province,China,(2020J011126) the China Postdoctoral Science Foundation(2021T140468) 

主　　题：N^(6)-methyladenosine Centromere protein K Cervical cancer Stemness Chemoresistance 

摘      要：Background:Stemness and chemoresistance contribute to cervical cancer recurrence and *** the current study,we determined the relevant players and role of N^(6)-methyladenine(m^(6)A)RNA methylation in cervical cancer ***:The roles of m^(6)A RNA methylation and centromere protein K(CENPK)in cervical cancer were analyzed using bioinformatics *** RNA immunoprecipitation was adopted to detect m^(6)A modification of CENPK *** cervical cancer clinical samples,cell lines,and xenografts were used for analyzing gene expression and *** staining and the tumorsphere formation,clonogenic,MTT,and EdU assays were performed to determine cell stemness,chemoresistance,migration,invasion,and proliferation in HeLa and SiHa cells,*** blot analysis,co-immunoprecipitation,chromatin immunoprecipitation,and luciferase reporter,cycloheximide chase,and cell fractionation assays were performed to elucidate the underlying ***:Bioinformatics analysis of public cancer datasets revealed firm links between m^(6)A modification patterns and cervical cancer prognosis,especially through ZC3H13-mediated m^(6)A modification of CENPK *** expression was elevated in cervical cancer,associated with cancer recurrence,and independently predicts poor patient prognosis[hazard ratio=1.413,95%confidence interval=1.078−1.853,P=0.012].Silencing of CENPK prolonged the overall survival time of cervical cancer-bearing mice and improved the response of cervical cancer tumors to chemotherapy in vivo(P0.001).We also showed that CENPK was directly bound to SOX6 and disrupted the interactions of CENPK withβ-catenin,which promotedβ-catenin expression and nuclear translocation,facilitated p53 ubiquitination,and led to activation of Wnt/β-catenin signaling,but suppression of the p53 *** dysregulation ultimately enhanced the tumorigenic pathways required for cell stemness,DNA damage repair pathways necessary f