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ALKBH8-mediated codon-specific translation promotes colorectal tumorigenesis
Yu Qian1, Canlan Wu1, Saisai Wei2
1Department of Clinical Laboratory of Sir Run Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China.
Nature Communications
|October 13, 2025
Summary
AlkB homolog 8 (ALKBH8) is crucial for colorectal cancer progression by regulating gene translation. Inhibiting ALKBH8 shows promise for treating intestinal tumors.
Area of Science:
- Molecular Biology
- Oncology
- Gene Expression Regulation
Background:
- Translational control of gene expression is implicated in intestinal tumorigenesis.
- The role of tRNA modifications in colorectal cancer (CRC) pathogenesis is not well understood.
Purpose of the Study:
- To investigate the role of AlkB homolog 8 (ALKBH8), a tRNA methyltransferase, in colorectal cancer.
- To elucidate the mechanism by which ALKBH8 influences intestinal tumor development.
Main Methods:
- Utilized genetic ablation of ALKBH8 in Apcmin/+, AOM/DSS, and xenograft mouse models.
- Analyzed ribosome pausing at adenine-ending codons and mRNA translation efficiency.
- Performed rescue experiments to confirm the methyltransferase activity's role.
Main Results:
- ALKBH8 is a direct Wnt/β-catenin target and is upregulated in colorectal cancer.
- ALKBH8 deficiency suppresses intestinal tumor formation across multiple models.
- Loss of ALKBH8 causes ribosome pausing and impairs translation of specific mRNAs, including KRAS proto-oncogene.
Conclusions:
- ALKBH8-dependent mRNA translation is a critical driver of intestinal tumorigenesis.
- ALKBH8 represents a potential therapeutic target for colorectal cancer treatment.
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