ALKBH8-mediated codon-specific translation promotes colorectal tumorigenesis

作者：Qian Yu, Canlan Wu, Saisai Wei, Sujun Yan, Junxuan Peng, Lei Yu, Yong-zhong Gao, Jingyu Hou, Wentao Yu, Zhanghui Chen, Jun Zhang, Xiangwei Gao · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-64144-0 · 被引用次数：3 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、RNA and protein synthesis mechanisms

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. ALKBH8 is a tRNA methyltransferase, specifically modifying the wobble uridine (U34) in tRNAs. Here, the authors discover that ALKBH8 is a direct transcriptional target of β-catenin, and that mediates intestinal tumorigenesis through regulation of the translation of KRAS in a codon-dependent manner.