NUDT21 的非甲基化抑制了二十二碳六烯酸的生物合成,导致前列腺癌对恩杂鲁胺产生耐药性

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Resistance Updates Pub Date : 2024-08-24 DOI:10.1016/j.drup.2024.101144
Shin-Chih Lin , Ya-Chuan Tsai , Ying-Lan Chen , Hui-Kuan Lin , Yun-Chen Huang , Yi-Syuan Lin , Yu-Sheng Cheng , Hsing-Yi Chen , Chia-Jung Li , Tsung-Yen Lin , Shih-Chieh Lin
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引用次数: 0

摘要

目的最近恩杂鲁胺被批准用于治疗转移性阉割敏感性前列腺癌,这凸显了它日益增长的临床意义,同时也引起了人们对新出现的耐药性和治疗选择有限的担忧。虽然雄激素受体(AR)和其他基因的重新激活在恩扎鲁胺耐药性中起着一定作用,但在恩扎鲁胺耐药(EnzaR)细胞中发现具有治疗潜力的新的潜在机制在很大程度上仍是未知数。方法利用耐药前列腺癌细胞系、动物模型和器官组织,通过功能缺失和功能增益试验,通过转录组和代谢组分析来研究NUDT21的功能。结果NUDT21过表达是一种关键的替代多腺苷酸化(APA)介导因子,它在前列腺癌中的致癌作用支持了这一点。PRMT7 介导的 NUDT21 单甲基化诱导了 3'UTR 使用的转变,从而降低了致癌性。相反,NUDT21 的非甲基化会通过输出有毒铜和抑制二十二碳六烯酸(DHA)的生物合成,促进 EnzaR 细胞的癌症生长和杯突症不敏感性。结论NUDT21介导的3'UTR缩短的非甲基化揭示了恩杂鲁胺耐药的新机制,我们的发现为推进恩杂鲁胺耐药前列腺癌患者的治疗提供了创新策略。
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Un-methylation of NUDT21 represses docosahexaenoic acid biosynthesis contributing to enzalutamide resistance in prostate cancer

Aims

The recent approval of enzalutamide for metastatic castration-sensitive prostate cancer underscores its growing clinical significance, raising concerns about emerging resistance and limited treatment options. While the reactivation of the androgen receptor (AR) and other genes plays a role in enzalutamide resistance, identifications of novel underlying mechanism with therapeutic potential in enzalutamide-resistant (EnzaR) cells remain largely elusive.

Methods

Drug-resistant prostate cancer cell lines, animal models, and organoids were utilized to examine NUDT21 function by transcriptomic and metabolomic analyses through loss-of-function and gain-of-function assays. Notably, a mono-methylation monoclonal antibody and conditional-knockin transgenic mouse model of NUDT21 were generated for evaluating its function.

Results

NUDT21 overexpression acts as a crucial alternative polyadenylation (APA) mediator, supported by its oncogenic role in prostate cancer. PRMT7-mediated mono-methylation of NUDT21 induces a shift in 3’UTR usage, reducing oncogenicity. In contrast, its un-methylation promotes cancer growth and cuproptosis insensitivity in EnzaR cells by exporting toxic copper and suppressing docosahexaenoic acid (DHA) biosynthesis. Crucially, NUDT21 inhibition or DHA supplementation with copper ionophore holds therapeutic promise for EnzaR cells.

Conclusions

The un-methylation of NUDT21-mediated 3’UTR shortening unveils a novel mechanism for enzalutamide resistance, and our findings offer innovative strategies for advancing the treatment of prostate cancer patients experiencing enzalutamide resistance.

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来源期刊
Drug Resistance Updates
Drug Resistance Updates 医学-药学
CiteScore
26.20
自引率
11.90%
发文量
32
审稿时长
29 days
期刊介绍: Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research
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