METTL3-based epitranscriptomic editing screening identifies functional m⁶A sites in cancers.

Area of Science:

• Epitranscriptomics
• Cancer Biology
• Molecular Oncology

Background:

• N⁶-methyladenosine (m⁶A) is the most prevalent internal RNA modification, regulating gene expression.
• While m⁶A is linked to cancer, its functional role across the entire transcriptome is not fully understood.

Purpose of the Study:

• To develop a platform for functional epitranscriptomic screening.
• To identify m⁶A sites that regulate cancer cell proliferation.
• To elucidate the mechanism of a novel tumor-suppressive m⁶A modification in prostate cancer.

Main Methods:

• Development of a targeted m⁶A deposition screening platform.
• Application of the platform in prostate and lung cancer models.
• Functional characterization of m⁶A sites, including mechanistic studies involving protein interactions and signaling pathways.

Main Results:

• Identification of 222 m⁶A sites influencing cell proliferation in a cell-type-specific manner.
• Discovery of a tumor-suppressive m⁶A site in CHD9 in prostate cancer.
• Demonstration that m⁶A at this site enhances CHD9 protein levels, suppresses proliferation, and involves YTHDF1/3, MYBBP1A sequestration, and CDKN1A activation.

Conclusions:

• The study presents a scalable framework for functional m⁶A epitranscriptome mapping.
• A novel mechanism linking CHD9 m⁶A modification to tumor suppression in prostate cancer is uncovered.
• This work opens avenues for exploring other RNA modifications in cancer therapeutics.