2. Academic Validation
  3. RNA m1A methyltransferase TRMT61A promotes colorectal tumorigenesis by enhancing ONECUT2 mRNA stability and is a potential therapeutic target

RNA m1A methyltransferase TRMT61A promotes colorectal tumorigenesis by enhancing ONECUT2 mRNA stability and is a potential therapeutic target

  • Cancer Commun (Lond). 2025 Oct 16. doi: 10.1002/cac2.70070.
Xiaoting Zhang 1 2,  Na Qin 1 2,  Fenfen Ji 2,  Hao Su 1 2,  Haiyun Shang 1 2,  Hongyan Chen 1 2,  Dan Huang 1,  Qing Li 1 2,  Jing Ren 1 2,  Weixin Liu 2,  Yifei Wang 3,  Wei Kang 3,  Jiabin Wu 4,  Chi-Chun Wong 2,  Zongwei Cai 4,  Matthew Tak Vai Chan 1,  William Ka Kei Wu 1 2,  Jun Yu 2,  Huarong Chen 1 2
Affiliations

Affiliations

  • 1 Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, P. R. China.
  • 2 Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, P. R. China.
  • 3 Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, The Chinese University of Hong Kong, Hong Kong, P. R. China.
  • 4 State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong, P. R. China.
PMID: 41103012 DOI: 10.1002/cac2.70070
Abstract

Background: The role of N1-methyladenosine (m1A) in Cancer is poorly understood. Here we explored the function of RNA methyltransferase TRNA methyltransferase 61A (TRMT61A) in colorectal Cancer (CRC) and its potential as a therapeutic target.

Methods: RNA m1A levels were assessed through liquid chromatography-mass spectrometry. The expression and clinical significance of TRMT61A were investigated across five human CRC cohorts. The function of TRMT61A was elucidated using CRC cell lines, patient-derived organoids, xenografts, and transgenic mouse models. Integrated analyses of m1A-sequencing and RNA-sequencing revealed the underlying mechanisms of TRMT61A. A nanoparticle-based small interfering RNA (siRNA) delivery system and a specific inhibitor were developed to target TRMT61A. The efficacy and safety of targeting TRMT61A were assessed.

Results: Our research revealed a consistent increase in TRMT61A expression and total RNA m1A levels within primary CRCs. High TRMT61A expression was associated with poor prognosis of CRC patients. Through CRISPR/Cas9 screenings, we identified TRMT61A as the most essential gene among m1A regulators. Furthermore, we established that TRMT61A promoted CRC tumorigenesis and progression by enhancing the mRNA stability of critical targets in an m1A-dependent manner. In particular, TRMT61A boosted the mRNA stability of one cut homeobox 2 (ONECUT2), which in turn triggered son of sevenless homolog 1 (SOS1) transcription, leading to the induction of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling in CRC. Notably, our study underscored the safety and substantial anti-CRC effects achievable by inhibiting TRMT61A using nanoparticle-encapsulated siTRMT61A or our newly discovered small molecule compound, pentagalloylglucose.

Conclusions: Our study unveiled the tumor-promoting role of TRMT61A in CRC via the m1A-ONECUT2-SOS1-MAPK/ERK pathway. Targeting TRMT61A showed promise as a therapeutic strategy for treating CRC.

Keywords

Colorectal Cancer; MAPK/ERK; N1‐Methyladenosine; TRMT61A; Therapeutic target.

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