METTL3 orchestrates cancer progression by m6A-dependent modulation of oncogenic lncRNAs

RNA modifications, particularly N⁶-methyladenosine (m⁶A), play crucial roles in gene expression regulation. While extensively studied in the context of mRNA, the impact of m⁶A on long non-coding RNAs (lncRNAs) remains elusive. This research aimed to reveal the regulatory landscape of m⁶A in lncRNA expression. In a comprehensive analysis across 6219 samples spanning 12 cancer types, we unveiled METTL3 as the most potent regulator of lncRNA expression among the examined 19 m⁶A regulators. A total of 397 METTL3-mediated m⁶A-modified lncRNAs (mmlncRs) were unveiled across 12 cancer types, indicating a consistent mechanism of METTL3-mediated lncRNA regulation. Functional assays demonstrated that METTL3 knockout significantly impeded lung cancer cell proliferation and progression. Leveraging RNA-seq and MeRIP-seq, we identified C1RL-AS1 as a bona fide m⁶A target of METTL3 in lung cancer, revealing its oncogenic role. Mechanistically, METTL3 depletion disrupts m⁶A modification on C1RL-AS1, leading to its downregulated expression. YTHDF2 binds to C1RL-AS1, maintaining its stability in a m⁶A-dependent manner. This study provides a valuable resource for the exploration of mmlncRs as promising therapeutic targets in cancers, shedding light on the intricate regulatory networks orchestrated by METTL3.