2. Academic Validation
  3. METTL3 orchestrates cancer progression by m6A-dependent modulation of oncogenic lncRNAs

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

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: 20231099@hznu.edu.cn.
  • 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: yanlu76@zju.edu.cn.
  • 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: pyliu@zju.edu.cn.
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.

Figures
Products