ALKBH8-mediated codon-specific translation promotes colorectal tumorigenesis

Yu Qian, Canlan Wu, Saisai Wei, Sujun Yan, Junxuan Peng, Lei Yu, Yunyi Gao, Jingyu Hou, Wentao Yu, Zhanghui Chen (), Jun Zhang () and Xiangwei Gao ()
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Yu Qian: Zhejiang University School of Medicine
Canlan Wu: Zhejiang University School of Medicine
Saisai Wei: Zhejiang University School of Medicine
Sujun Yan: Zhejiang University School of Medicine
Junxuan Peng: Zhejiang University School of Medicine
Lei Yu: Zhejiang University School of Medicine
Yunyi Gao: Zhejiang University School of Medicine
Jingyu Hou: Zhejiang University School of Medicine
Wentao Yu: Zhejiang University School of Medicine
Zhanghui Chen: Zhanjiang Central Hospital
Jun Zhang: Zhejiang University School of Medicine
Xiangwei Gao: Zhejiang University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64144-0

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