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

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

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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.

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

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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

University of Chinese Academy of Sciences,Beijing,China

Shanghai Institute of Thoracic Oncology,Shanghai Chest Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,China

Human Oncology and Pathogenesis Program,Department of Medicine,Memorial Sloan Kettering Cancer Center,New York,NY,USA

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

Department of Urology,The First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu,China

Institute of Cancer Research,Shenzhen Bay Laboratory,Shenzhen,Guangdong,China

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2025

10.1038/s41422-024-01025-z

细胞研究(英文版)
中国科学院上海生化细胞所

细胞研究(英文版)

影响因子：1.355
ISSN：
年,卷(期)：2025.35(1)