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  3. The AHCY-adenosine complex rewires mRNA methylation to enhance fatty acid biosynthesis and tumorigenesis

The AHCY-adenosine complex rewires mRNA methylation to enhance fatty acid biosynthesis and tumorigenesis

  • Cell Res. 2026 Feb;36(2):152-172. doi: 10.1038/s41422-025-01213-5.
Kun Liao # 1,  Fen Cao # 2,  Chen Wei # 1,  Zheng-Yu Qian # 1,  Hong-Rong Hu 3,  Wen-Feng Pan 3,  Zi-Qing Feng 1,  Sen-Mao Lian 1,  Zi-Xuan Xiao 1,  Hui Sheng 1,  Hai-Yu Mo 1,  Yi-Xuan Zhao 4,  Qi-Nian Wu 1,  Zhao-Lei Zeng 1 5,  Bo Li 6 7 8,  Rui-Hua Xu 9 10 11,  Huai-Qiang Ju 12 13
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 2 Department of Urology, Guangdong Provincial People's Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 3 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 4 Department of Biochemistry and Molecular Biology, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
  • 5 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong, China.
  • 6 Department of Urology, Guangdong Provincial People's Hospital, Southern Medical University, Guangzhou, Guangdong, China. [email protected].
  • 7 Department of Biochemistry and Molecular Biology, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. [email protected].
  • 8 Experimental Education and Administration Center, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. [email protected].
  • 9 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected].
  • 10 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong, China. [email protected].
  • 11 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected].
  • 12 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected].
  • 13 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong, China. [email protected].
  • # Contributed equally.
PMID: 41549122 DOI: 10.1038/s41422-025-01213-5
Abstract

Methionine metabolism generates the substrate S-adenosylmethionine (SAM), which regulates epigenetic modifications crucial for various cellular processes, particularly tumorigenesis. However, whether methionine metabolism involves epigenetic mechanisms independent of SAM and what roles such mechanisms play in tumorigenesis remain unclear. We show here that the adenosylhomocysteinase (AHCY)-adenosine complex increases mRNA m6A levels in a non-global manner, promoting fatty acid synthesis and tumorigenesis. Adenosine increases mRNA m6A levels by binding to the methionine metabolism enzyme AHCY to form a complex, rather than depending on adenosine receptors. The AHCY-adenosine complex facilitates AHCY dimerization, with adenosine being crucial for dimer stability. AHCY dimers hinder the binding of fat mass and obesity-associated protein (FTO) at the Q86 site to RNA containing the VWDRACH motif, increasing m6A levels and upregulating lipogenesis genes, especially ACACA and SCD1, thus leading to reprogramming of lipid metabolism. Conversely, AHCY mutants that have lost dimerization or FTO-binding ability but retain hydrolase activity suppress lipogenesis and tumor growth without significantly affecting methionine catabolism mediated by AHCY. Loss of AHCY in mice and disruption of AHCY dimerization in tumor cells and patient-derived xenograft models restricted tumor growth. Our findings demonstrate a key SAM-independent link between methionine metabolism and mRNA m6A modification that affects demethylase substrate specificity. This novel link between the methionine cycle and lipid metabolism suggests new strategies for Anticancer therapy.

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