N1-Methyladenosine (m1A) is a prevalent RNA modification that governs RNA metabolism, structure, stability, and translation. Yet its cancer-wide landscape and functional impact remain largely unexplored. Here, we delineate the m1A regulatory network in lung squamous cell carcinoma (LUSC). The dominant m1A writer of TRMT6 emerged as the most up-regulated regulator in LUSC through a comprehensive pan-cancer analysis; both TRMT6 expression and global m1A levels significantly distinguished LUSC from normal tissue, serving as potent diagnostic biomarkers. Functionally, TRMT6 installs m1A marks and facilitates their cellular export. Both the in vitro and in vivo experiments reveal that TRMT6 accelerates LUSC proliferation by orchestrating cell-cycle gene expression. Mechanistically, TRMT6 binds cell-cycle transcripts, most notably TOPBP1 and DSN1, promotes the formation of m1A, and stabilizes these mRNAs via the YTHDF3 reader pathway. A single, critical m1A site in each target mRNA is sufficient to boost TOPBP1 and DSN1 expression. Using dCasRx-TRMT6, we further show that site-specific m1A deposition on DSN1 mRNA is a potent strategy to modulate its expression and drive proliferation. Collectively, our findings uncover a previously unrecognized m1A-dependent regulatory axis that underpins LUSC diagnosis and progression.
Xue et al. (Tue,) studied this question.