ALKBH8-mediated codon-specific translation promotes colorectal tumorigenesis.

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-10-13 DOI:10.1038/s41467-025-64144-0

Yu Qian,Canlan Wu,Saisai Wei,Sujun Yan,Junxuan Peng,Lei Yu,Yunyi Gao,Jingyu Hou,Wentao Yu,Zhanghui Chen,Jun Zhang,Xiangwei Gao

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Abstract

Reprogramming gene expression at the translational level drives intestinal tumorigenesis. Codon decoding during translation elongation relies on tRNA modifications, while their pathological relevance in colorectal cancer remains to be elucidated. Here, we show that AlkB homolog 8 (ALKBH8), a uridine 34 (U34) tRNA methyltransferase, is a direct target of Wnt/β-catenin and is upregulated in colorectal cancer. Genetic ablation of ALKBH8 inhibits the development of intestinal tumors in Apcmin/+, azoxymethane/dextran sulfate sodium (AOM/DSS), and xenograft models. Loss of ALKBH8 induces ribosome pausing at adenine-ending codons, impairing the translation elongation of mRNAs enriched with these codons. Specifically, ALKBH8 regulates the translation of KRAS proto-oncogene in a codon-dependent manner. Rescue experiments demonstrate that the methyltransferase activity of ALKBH8 is required for its translation-promoting function. Together, our findings reveal ALKBH8-dependent mRNA translation as a critical mediator of intestinal tumorigenesis, underscoring its potential as a promising target for colorectal cancer therapy.

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alkbh8介导的密码子特异性翻译促进结直肠癌的发生。

在翻译水平上重编程基因表达驱动肠道肿瘤发生。翻译延伸过程中的密码子解码依赖于tRNA修饰，而其在结直肠癌中的病理相关性仍有待阐明。在这里，我们发现AlkB同源物8 (ALKBH8)，一种尿苷34 (U34) tRNA甲基转移酶，是Wnt/β-catenin的直接靶点，并且在结直肠癌中上调。在Apcmin/+、偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）和异种移植模型中，基因消融ALKBH8可抑制肠道肿瘤的发展。ALKBH8的缺失诱导核糖体在腺嘌呤末端密码子处暂停，从而削弱富含这些密码子的mrna的翻译延伸。具体来说，ALKBH8以密码子依赖的方式调节KRAS原癌基因的翻译。救援实验表明，ALKBH8的甲基转移酶活性是其翻译促进功能的必要条件。总之，我们的研究结果揭示了alkbh8依赖性mRNA翻译是肠道肿瘤发生的关键介质，强调了其作为结直肠癌治疗的有希望靶点的潜力。

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

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.