NSUN2 mediates intestinal stem cell expansion and colorectal tumour initiation via MAPK/ERK signalling

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Colorectal cancer (CRC) initiation involves the expansion of LGR5+ intestinal stem cells (ISCs) upon loss of APC.
• Regulation of ISC expansion during tumor initiation is not fully understood.
• Post-transcriptional RNA modifications are increasingly recognized for their role in cancer, but their specific involvement in CRC initiation remains unexplored.

Purpose of the Study:

• To identify key regulators of ISC expansion in colorectal cancer initiation.
• To investigate the role of RNA modifications, specifically m5C methylation, in CRC development.
• To elucidate the molecular mechanisms linking RNA methylation to stem cell transformation in CRC.

Main Methods:

• Utilized multiple CRC mouse models and human tumor samples.
• Performed transcriptome-wide bisulfite sequencing to map m5C methylation sites.
• Assessed the impact of NSUN2 depletion on ISC expansion, proliferation, and tumor initiation.
• Analyzed MAPK/ERK pathway signaling through Western blotting for ERK phosphorylation.

Main Results:

• NSUN2, an m5C methyltransferase, was found to be upregulated in CRC models and human tumors.
• NSUN2 depletion significantly impaired ISC expansion and hyperproliferation, reducing tumor initiation.
• NSUN2 mediates m5C methylation on mRNAs crucial for ISC regulation and the MAPK/ERK pathway.
• Loss of NSUN2 reduced ERK phosphorylation in Apc-deficient models, which was rescued by oncogenic Kras expression.

Conclusions:

• NSUN2 is a critical regulator of ISC-driven CRC initiation.
• NSUN2 links m5C RNA methylation to MAPK/ERK signaling in stem cell transformation.
• Targeting NSUN2 may offer a novel therapeutic strategy for colorectal cancer.