LKB1 inactivation promotes epigenetic remodeling-induced lineage plasticity and antiandrogen resistance in prostate cancer  

作　　者：Fei Li Pengfei Dai Huili Shi Yajuan Zhang Juan He Anuradha Gopalan Dan Li Yu Chen Yarui Du Guoliang Xu Weiwei Yang Chao Liang Dong Gao 

机构地区：[1]Key Laboratory of Multi-Cell Systems,Shanghai Key Laboratory of Molecular Andrology,Center for Excellence in Molecular Cell Science,Shanghai Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences,Shanghai,China [2]University of Chinese Academy of Sciences,Beijing,China [3]Shanghai Institute of Thoracic Oncology,Shanghai Chest Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,China [4]Human Oncology and Pathogenesis Program,Department of Medicine,Memorial Sloan Kettering Cancer Center,New York,NY,USA [5]Key Laboratory of Systems Health Science of Zhejiang Province,School of Life Science,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou,Zhejiang,China [6]Department of Urology,The First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu,China [7]Institute of Cancer Research,Shenzhen Bay Laboratory,Shenzhen,Guangdong,China

出　　处：《Cell Research》2025年第1期59-71,共13页细胞研究(英文版)

基　　金：supported by the National Science Fund for Distinguished Young Scholars(32125013);the Excellent Young Scholars Fund(82422052);the National Natural Science Foundation of China(92253304,82002718,92357301,92253305,82461160322);the National Key R&D Program of China(2023YFC2506401);the Jiangsu Natural Science Foundation(BK20191077);the China National Postdoctoral Program for Innovative Talents(BX2021306,BX2024370);the Shanghai Oriental Talent Program,Shanghai Science and Technology Development Funds(22QA1409900,23ZR1470100);Shanghai Municipal Science and Technology Major Project,the Sanofi Scholarship and Heaye Program.

摘　　要：Epigenetic regulation profoundly influences the fate of cancer cells and their capacity to switch between lineages by modulating essential gene expression,thereby shaping tumor heterogeneity and therapy response.In castration-resistant prostate cancer(CRPC),the intricacies behind androgen receptor(AR)-independent lineage plasticity remain unclear,leading to a scarcity of effective clinical treatments.Utilizing single-cell RNA sequencing on both human and mouse prostate cancer samples,combined with whole-genome bisulfite sequencing and multiple genetically engineered mouse models,we investigated the molecular mechanism of AR-independent lineage plasticity and uncovered a potential therapeutic strategy.Single-cell transcriptomic profiling of human prostate cancers,both pre-and post-androgen deprivation therapy,revealed an association between liver kinase B1(LKB1)pathway inactivation and AR independence.LKB1 inactivation led to AR-independent lineage plasticity and global DNA hypomethylation during prostate cancer progression.Importantly,the pharmacological inhibition of TET enzymes and supplementation with S-adenosyl methionine were found to effectively suppress AR-independent prostate cancer growth.These insights shed light on the mechanism driving AR-independent lineage plasticity and propose a potential therapeutic strategy by targeting DNA hypomethylation in AR-independent CRPC.

关 键 词：LKB1 INACTIVATION PLASTICITY 

分 类 号：R737.25[医药卫生—肿瘤] R394[医药卫生—临床医学]