2. Academic Validation
  3. ALKBH8-mediated codon-specific translation promotes colorectal tumorigenesis

ALKBH8-mediated codon-specific translation promotes colorectal tumorigenesis

  • Nat Commun. 2025 Oct 13;16(1):9075. doi: 10.1038/s41467-025-64144-0.
Yu Qian # 1,  Canlan Wu # 1,  Saisai Wei # 2,  Sujun Yan 1,  Junxuan Peng 1,  Lei Yu 1,  Yunyi Gao 1,  Jingyu Hou 1,  Wentao Yu 1,  Zhanghui Chen 3,  Jun Zhang 4,  Xiangwei Gao 5
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory of Sir Run Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Zhanjiang Institute of Clinical Medicine, Zhanjiang Central Hospital, Zhanjiang, China. [email protected].
  • 4 Department of Clinical Laboratory of Sir Run Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 5 Department of Clinical Laboratory of Sir Run Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41083459 DOI: 10.1038/s41467-025-64144-0
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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