The Nα-acetyl-L-lysine/Loxl2/H2O2 promotes intestinal tumor growth in Drosophila and cell proliferation in human colorectal cancer

  • Cell Rep. 2025 Aug 26;44(8):116126. doi: 10.1016/j.celrep.2025.116126.
Lei Geng  1 ,  Zhen Fan  2 ,  Rongbing Chen  2 ,  Kyu-Chan Cho  3 ,  Yining Liu  4 ,  Yu Cheng  5 ,  Jingfeng Yang  2 ,  Ying Zhang  2 ,  Xuefei Wei  2 ,  Liyuan Gong  2 ,  Yingyu Tang  2 ,  Zhan Xu  6 ,  Wuren Huang  2 ,  Shahzad Toufeeq  2 ,  Zongzhao Zhai  7 ,  Lei Pan  8 ,  Jun Zhang  5 ,  Bin Li  6 ,  Brenda T Beerntsen  9 ,  Ji-Hoon Lee  3 ,  Youli Xiao  2 ,  Younghwa Na  10 ,  Won-Jae Lee  11 ,  Erjun Ling  12
Affiliations
  • 1. University of Chinese Academy of Sciences, Beijing 101408, China; CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200036, China.
  • 2. CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200036, China.
  • 3. School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
  • 4. eCore Facility Centre, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200036, China.
  • 5. State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China.
  • 6. Shanghai Institute of Immunology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 7. Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha 410081, China.
  • 8. The Center for Microbes, Development, and Health, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200036, China.
  • 9. Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, USA.
  • 10. College of Pharmacy, CHA University, Pochon 11160, Republic of Korea. Electronic address: [email protected].
  • 11. School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: [email protected].
  • 12. CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200036, China. Electronic address: [email protected].
PMID: 40811058 DOI: 10.1016/j.celrep.2025.116126
Abstract

A cancer-associated microbiome is considered a carcinogen capable of affecting tumor initiation and/or progression. However, little is known about the molecular mechanisms of tumor-microbiome interactions. Here, we show that Staphylococcus sciuri promotes Drosophila intestinal tumor growth by inducing intestinal stem cell (ISC) division. Metabolomic analysis revealed that Nα-acetyl-L-lysine derived from S. sciuri, but not Other naturally Nα-acetylated L-type Amino acids, promotes ISC division in germ-free and conventional Animals. Biochemical analysis further shows that GCN5-related N-acetyl transferases of S. sciuri catalyze L-lysine and acetyl-CoA into Nα-acetyl-L-lysine. Drosophila lysyl oxidase-like 2 enzyme subsequently catalyzes Nα-acetyl-L-lysine to produce H2O2, forming the Nα-acetyl-L-lysine/Loxl2/H2O2 axis that activates ATR-Chk1 and JNK and subsequently triggers the JAK/STAT pathway required for ISC division and tumor growth. The Nα-acetyl-L-lysine/Loxl2/H2O2 axis also regulates human colorectal Cancer cell division. The identification of Nα-acetyl-L-lysine/Loxl2/H2O2 axis provides distinct insights into the complex interplay among microbiome, tumor, and oxidative stress.

Keywords
ATR-Chk1 pathway; CP: Cancer; CP: Microbiology; Drosophila; JAK/STAT pathway; JNK pathway; Nα-acetyl-L-lysine/Loxl2/H(2)O(2) axis; Staphylococcus sciuri; colorectal cancer cell; intestinal stem cell; microbiome-tumor-H₂O₂ interplay.
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