A cancer-associated METTL14 mutation induces aberrant m6A modification, affecting tumor growth

Area of Science:

• Molecular Biology
• Epigenetics
• Cancer Research

Background:

• The METTL3/METTL14 complex is crucial for N6-methyladenosine (m6A) modification, influencing mRNA stability.
• The METTL14 R298P mutation is observed in various cancers, but its functional impact remains unclear.

Purpose of the Study:

• To investigate the biological effects of the METTL14 R298P mutation on cancer cell proliferation and m6A modification patterns.

Main Methods:

• Utilized cell line models with heterozygous and homozygous METTL14 R298P mutations.
• Performed methylated RNA immunoprecipitation sequencing (MeRIP-seq) to analyze m6A modification sites.
• Quantified gene expression levels, including c-Myc.

Main Results:

• Heterozygous R298P mutation promotes cancer cell proliferation; homozygous mutation reduces it.
• The R298P mutation decreases m6A at canonical sites but induces it at aberrant sites in homozygous cells.
• Aberrant m6A recognition alters methylation at nearby canonical sites, exemplified by c-MET mRNA destabilization.

Conclusions:

• The METTL14 R298P mutation disrupts m6A target recognition, leading to altered gene expression and cell growth.
• This mutation affects mRNA stability and downstream protein expression, impacting cancer progression.