LKB1失活促进前列腺癌表观遗传重塑诱导的谱系可塑性和抗雄激素抗性

IF 28.1 1区 生物学 Q1 CELL BIOLOGY Cell Research Pub Date : 2025-01-02 DOI:10.1038/s41422-024-01025-z
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
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摘要

表观遗传调控通过调节基本基因表达深刻地影响癌细胞的命运及其在谱系之间切换的能力,从而塑造肿瘤的异质性和治疗反应。在去势抵抗性前列腺癌(CRPC)中,雄激素受体(AR)独立谱系可塑性背后的复杂性仍然不清楚,导致缺乏有效的临床治疗。利用人类和小鼠前列腺癌样本的单细胞RNA测序,结合全基因组亚硫酸盐测序和多种基因工程小鼠模型,我们研究了ar不依赖谱系可塑性的分子机制,并发现了一种潜在的治疗策略。人类前列腺癌,雄激素剥夺治疗前后的单细胞转录组学分析显示,肝激酶B1 (LKB1)途径失活与AR独立性之间存在关联。在前列腺癌进展过程中,LKB1失活导致ar非依赖性谱系可塑性和整体DNA低甲基化。重要的是,发现TET酶的药理抑制和补充s -腺苷蛋氨酸可有效抑制ar非依赖性前列腺癌的生长。这些发现揭示了ar非依赖性谱系可塑性的驱动机制,并提出了一种潜在的治疗策略,即靶向ar非依赖性CRPC中的DNA低甲基化。
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LKB1 inactivation promotes epigenetic remodeling-induced lineage plasticity and antiandrogen resistance in prostate cancer
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.
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来源期刊
Cell Research
Cell Research 生物-细胞生物学
CiteScore
53.90
自引率
0.70%
发文量
2420
审稿时长
2.3 months
期刊介绍: Cell Research (CR) is an international journal published by Springer Nature in partnership with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). It focuses on publishing original research articles and reviews in various areas of life sciences, particularly those related to molecular and cell biology. The journal covers a broad range of topics including cell growth, differentiation, and apoptosis; signal transduction; stem cell biology and development; chromatin, epigenetics, and transcription; RNA biology; structural and molecular biology; cancer biology and metabolism; immunity and molecular pathogenesis; molecular and cellular neuroscience; plant molecular and cell biology; and omics, system biology, and synthetic biology. CR is recognized as China's best international journal in life sciences and is part of Springer Nature's prestigious family of Molecular Cell Biology journals.
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