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

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

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: yna7315@cha.ac.kr.
  • 11 School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: lwj@snu.ac.kr.
  • 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: erjunling@cemps.ac.cn.
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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