ALKBH5-IGF2BP2 axis mediates prostate cancer progression and docetaxel resistance via m6A-stabilized CLSPN RNA

IF 4.1 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-09-09 DOI:10.1016/j.isci.2025.113520

Yutong Chen , Yang Li , Zongzhu Liang , Zhao Yang , Haotian Ren , Wanqing Wei , Yuanjie Niu , Zhiqun Shang

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Abstract

Prostate cancer (PCa) often progresses to castration-resistant PCa (CRPC), where docetaxel (DTX) resistance is a major challenge. We investigated the role of the m6A demethylase ALKBH5 in this resistance. ALKBH5 expression was significantly reduced in CRPC clinical samples. Functionally, overexpressing ALKBH5 inhibited PCa cell proliferation and migration, while its knockdown enhanced these effects and increased DTX resistance. Conversely, restoring ALKBH5 or knocking down the m6A reader IGF2BP2 reversed resistance. Multi-omics analysis identified CLSPN, a DNA replication stress regulator, as a key downstream target. Mechanistically, ALKBH5-mediated m6A demethylation reduces CLSPN mRNA stability in an IGF2BP2-dependent manner. Low ALKBH5, therefore, stabilizes CLSPN via IGF2BP2, promoting resistance. These findings, validated in clinical samples and organoid models, demonstrate that the ALKBH5-IGF2BP2 axis modulates DTX resistance in metastatic CRPC through m6A-dependent regulation of CLSPN. Targeting this pathway represents a promising therapeutic strategy to overcome DTX resistance.

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ALKBH5-IGF2BP2轴通过m6a稳定的CLSPN RNA介导前列腺癌进展和多西他赛耐药

前列腺癌（PCa）经常发展为去势抵抗性前列腺癌（CRPC），其中多西他赛（DTX）耐药性是一个主要挑战。我们研究了m6A去甲基化酶ALKBH5在这种耐药性中的作用。在CRPC临床样本中，ALKBH5的表达显著降低。功能上，ALKBH5过表达抑制了PCa细胞的增殖和迁移，而敲低ALKBH5则增强了这些作用，并增加了对DTX的抗性。相反，恢复ALKBH5或敲低m6A阅读器IGF2BP2的反向电阻。多组学分析发现，DNA复制应激调节因子CLSPN是一个关键的下游靶点。机制上，alkbh5介导的m6A去甲基化以依赖igf2bp2的方式降低CLSPN mRNA的稳定性。因此，低ALKBH5通过IGF2BP2稳定CLSPN，促进抗性。这些发现在临床样本和类器官模型中得到验证，表明ALKBH5-IGF2BP2轴通过m6a依赖性CLSPN调控转移性CRPC的DTX耐药性。靶向这一途径是克服DTX耐药的一种有希望的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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