METTL1-mediated m7G tRNA modification promotes colorectal cancer progression and liver metastasis via translational regulation

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with colorectal cancer liver metastasis (CRLM) being the primary cause of death. Despite its clinical significance, the molecular mechanisms underlying CRC progression remain poorly understood. METHODS: Unbiased proteomic profiling and single-cell RNA sequencing (scRNA-seq) analyses of CRC tissues from patients with and without liver metastases identified methyltransferase-like protein 1 (METTL1) as a critical regulator, with its function in CRC progression validated through in vitro and in vivo gain- and loss-of-function studies. Furthermore, tRNA methylation sequencing (TRAC-seq) and ribosome-nascent chain complex sequencing (RNC-seq) were performed to investigate the downstream mechanisms. RESULTS: METTL1 was significantly elevated in CRC, with the highest expression in CRLM, and correlated with poor survival. METTL1 knockout inhibited tumor cell proliferation, migration, and invasion in vitro, whereas overexpression of wild-type METTL1, but not its catalytically inactive mutant, promoted oncogenic phenotypes. Consistently, METTL1 knockout attenuated tumor growth and liver metastasis in vivo. Mechanistically, METTL1-mediated m7G tRNA modification selectively enhanced translation of oncogenic transcripts, particularly those involved in cell cycle regulation (e.g., CCND3) and PI3K/Akt signaling. Notably, forced CCND3 expression partially rescued the phenotypes induced by METTL1 knockout. CONCLUSIONS: Our findings highlight the crucial role of METTL1 and its tRNA m7G modification in promoting CRC progression and liver metastasis, providing promising targets for therapy in advanced CRC.