TRMT6-directed m1A modification initiates lung squamous cell carcinoma via YTHDF3-stabilized cell cycle genes

Abstract

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.