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

Rákkutatás · Colorectal cancer · KRAS

NSUN2 regulates the expansion of intestinal stem cells and initiates colorectal tumour formation through MAPK/ERK signalling.

Colorectal cancer is initiated by loss of APC, which drives expansion of LGR5+ intestinal stem cell (ISC) populations. Whilst LGR5+ ISC expansion is a critical step for tumour initiation and progression, its regulation is poorly understood. Emerging evidence suggests post‑transcriptional RNA modifications play a key role in cancer biology, but their role in CRC initiation has not been explored. Here, we identify the m5C methyltransferase NSUN2 as a key regulator of ISC expansion and intestinal tumourigenesis. NSUN2 is upregulated in multiple CRC mouse models and human tumours, and its depletion impairs ISC expansion and hyperproliferation, leading to reduced tumour initiation. Transcriptome‑wide bisulfite sequencing revealed that NSUN2 mediates m5C methylation on mRNAs encoding key ISC regulators and components of the MAPK/ERK pathway. Mechanistically, loss of NSUN2 reduces ERK phosphorylation in Apc‑deficient models, and oncogenic KRASG12D expression is sufficient to restore ERK signalling and rescue ISC expansion. Together, this establishes a novel role for NSUN2 as a key regulator of ISC‑driven CRC initiation and describes a critical molecular mechanism linking m5C methylation to MAPK‑driven stem cell transformation.

Colorectal cancer remains a leading cause of cancer mortality with limited treatment options due to therapy resistance and relapse driven by cancer stem cells. Identifying that the RNA methyltransferase NSUN2 drives ISC expansion and tumour initiation via MAPK/ERK signalling offers a new mechanistic insight that may inform targeted therapeutics and improve patient outcomes.

Bizonyítékszint: Korai humán adat. Kis vagy feltáró emberi adat.

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