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

Area of Science:

• Molecular Biology
• Cancer Research
• Epigenetics

Background:

• N⁶-methyladenosine (m⁶A) is a critical RNA modification impacting gene expression, primarily studied in mRNA.
• The role of m⁶A in regulating long non-coding RNAs (lncRNAs) is not well understood.
• Understanding m⁶A's influence on lncRNAs is essential for deciphering complex gene regulatory networks in diseases like cancer.

Purpose of the Study:

• To investigate the regulatory landscape of m⁶A modifications in lncRNA expression across various cancer types.
• To identify key m⁶A regulators and their target lncRNAs involved in cancer.
• To elucidate the functional and mechanistic roles of specific m⁶A-modified lncRNAs in cancer progression.

Main Methods:

• Comprehensive analysis of m⁶A regulators and lncRNAs across 6219 cancer samples from 12 types.
• Utilized RNA sequencing (RNA-seq) and m⁶A-specific immunoprecipitation sequencing (MeRIP-seq).
• Performed functional assays, including gene knockout experiments, to assess the impact of METTL3 on cancer cells.

Main Results:

• METTL3 was identified as the most significant regulator of lncRNA expression among 19 m⁶A regulators studied.
• Discovered 397 METTL3-mediated m⁶A-modified lncRNAs (mmlncRs) consistently across 12 cancer types.
• METTL3 knockout inhibited lung cancer cell proliferation; C1RL-AS1 was identified as an oncogenic m⁶A target of METTL3, with its stability dependent on YTHDF2 binding.

Conclusions:

• METTL3 plays a crucial role in lncRNA m⁶A modification and influences cancer progression.
• mmlncRs represent a novel class of regulatory molecules with potential as cancer biomarkers and therapeutic targets.
• This research provides a foundational resource for understanding METTL3-driven lncRNA regulation in oncology.