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<p>Colorectal cancer is initiated by loss of <i>APC</i>, 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 m<sup>5</sup>C 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 m<sup>5</sup>C methylation on mRNAs encoding key ISC regulators and components of the MAPK/ERK pathway. Mechanistically, loss of NSUN2 reduces ERK phosphorylation in <i>Apc-</i>deficient models, and oncogenic <i>Kras</i><sup><i>G12D</i></sup> 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 m<sup>5</sup>C methylation to MAPK-driven stem cell transformation.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月19日

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  • Aslihan Bastem Akan,
  • Caroline V. Billard,
  • Szu-Ying Chen,
  • Po-Hsien Huang,
  • Patrizia Cammareri,
  • Vidya Rajasekaran,
  • Adam E. Hall,
  • Paula Preyzner,
  • Sebastian Öther-Gee Pohl,
  • Susan M. Farrington,
  • Malcolm G. Dunlop,
  • Farhat V. N. Din,
  • Kevin B. Myant

摘要

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.