中国科学院分子细胞科学卓越创新中心高栋等研究人员合作发现，LKB1失活促进表观遗传重塑引发的谱系可塑性，和前列腺癌中的抗雄激素耐药性。相关论文于2025年1月2日在线发表在《细胞研究》杂志上。

通过在人类和小鼠前列腺癌样本上应用单细胞RNA测序，并结合全基因组亚硫酸盐测序和多种基因工程小鼠模型，研究人员揭示了雄激素受体（AR）非依赖性谱系可塑性的分子机制，并揭示了一种潜在的治疗策略。人类前列腺癌的单细胞转录组分析，无论是在雄激素剥夺治疗前还是治疗后，均揭示了肝激酶B1（LKB1）通路失活与AR非依赖性之间的关联。

LKB1失活导致前列腺癌进展过程中AR非依赖性的谱系可塑性和全基因组DNA低甲基化。重要的是，药理学抑制TET酶并补充S-腺苷甲硫氨酸被发现能有效抑制AR非依赖性前列腺癌的生长。这些发现揭示了驱动AR非依赖性谱系可塑性的机制，并通过靶向DNA低甲基化为AR非依赖性去势耐药型前列腺癌（CRPC）提出了一种潜在的治疗策略。

据了解，表观遗传调控深刻影响癌细胞的命运，及其通过调节关键基因表达在谱系之间切换的能力，从而塑造肿瘤异质性和治疗反应。在CRPC中，AR非依赖性谱系可塑性的复杂机制仍不清楚，这导致临床治疗手段的匮乏。

附：英文原文

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

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

Issue&Volume: 2025-01-02

Abstract: 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.

DOI: 10.1038/s41422-024-01025-z

Source: https://www.nature.com/articles/s41422-024-01025-z