Abstract 4100: Aberrant translation regulated by METTL1/WDR4-mediated Val-AAC tRNA N7-methylguanosine modification promotes gastric carcinogenesis

Background: Dysregulated epigenetic modifications in RNA are closely associated with the onset and progression of human tumors. Among cellular RNA modifications, transfer RNAs (tRNAs) are the most frequently modified type; however, the role of tRNA modifications in cancer remains largely unexplored. The RNA methyltransferase METTL1, which catalyzes N7-methylguanosine (m7G) modification of tRNAs, is often amplified and overexpressed in cancers and correlates with poor patient survival. In this study, we aimed to investigate the function and underlying mechanisms of m7G modification in tRNAs driving the development and progression of gastric cancer (GC). Methods: We conducted a series of mechanistic studies to investigate the physiological functions of tRNA m7G modifications in GC tumorigenesis. Using tRNA modification and expression profiling, mRNA translation profiling, and rescue assays, we identified the molecular mechanisms underlying m7G modification in GC. Additionally, we analyzed the expression levels of the tRNA m7G methyltransferase complex components, methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) in human GC samples. Results: METTL1/WDR4 promoted GC progression and metastasis in cell-based and xenograft mouse models. Mechanistically, the loss of METTL1 reduced tRNA m7G levels, particularly in Val-AAC tRNAs, leading to decreased translation of mRNAs enriched with m7G tRNA codons and impairing the synthesis of a subset of oncogenic transcripts. Moreover, the tRNA m7G methyltransferase complex components METTL1 and WDR4 were found to be upregulated in GC and correlated with poor patient prognosis. Conclusion: The tRNA m7G methyltransferase METTL1 was identified as a key driver of GC development and malignancy by regulating global mRNA translation through tRNA modifications. Our findings highlight METTL1 as a promising therapeutic target for GC patients. Citation Format: Yuan Li, Silei Sui, Rui Su, Ajay Goel. Aberrant translation regulated by METTL1/WDR4-mediated Val-AAC tRNA N7-methylguanosine modification promotes gastric carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4100.