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

  • Int J Biol Macromol. 2025 May;310(Pt 3):143299. doi: 10.1016/j.ijbiomac.2025.143299.
Xinyi Qian  1 ,  Xufan Li  1 ,  Zhihong Zheng  2 ,  Lian Liu  1 ,  Jia Li  1 ,  Juze Yang  1 ,  Bingjian Lu  2 ,  Enguo Chen  3 ,  Honghe Zhang  4 ,  Bo Ye  5 ,  Yan Lu  6 ,  Pengyuan Liu  7
Affiliations
  • 1. Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China.
  • 2. Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China.
  • 3. Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310013, China.
  • 4. Department of Pathology, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310013, China.
  • 5. Department of Thoracic Surgery, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310003, China. Electronic address: [email protected].
  • 6. Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310013, China; Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China. Electronic address: [email protected].
  • 7. Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310013, China; Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85724, USA; Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China. Electronic address: [email protected].
PMID: 40253016 DOI: 10.1016/j.ijbiomac.2025.143299
Abstract

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.

Keywords
C1RL-AS1; Cancer progression; LncRNA; METTL3; Pan-cancer analysis; RNA stability; YTHDF2; m(6)A modification.
Products