The Nα-acetyl-L-lysine/Loxl2/H2O2 promotes intestinal tumor growth in Drosophila and cell proliferation in human colorectal cancer
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 H<sub>2</sub>O<sub>2</sub>, forming the Nα-acetyl-L-lysine/Loxl2/H<sub>2</sub>O<sub>2</sub> 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/H<sub>2</sub>O<sub>2</sub> axis also regulates human colorectal cancer cell division. The identification of Nα-acetyl-L-lysine/Loxl2/H<sub>2</sub>O<sub>2</sub> axis provides distinct insights into the complex interplay among microbiome, tumor, and oxidative stress.
Authors
- Zhan Xu (ORCID: https://orcid.org/0000-0003-1224-9789)
- Kyu-Chan Cho (ORCID: https://orcid.org/0009-0004-8177-8275)
- Brenda T. Beerntsen (ORCID: https://orcid.org/0000-0003-0639-041X)
- Erjun Ling (ORCID: https://orcid.org/0000-0002-9916-0105)
- Ying-Yu Tang (ORCID: https://orcid.org/0009-0003-6954-7004)
- Zongzhao Zhai (ORCID: https://orcid.org/0000-0003-3987-7742)
- Younghwa Na (ORCID: https://orcid.org/0009-0004-7281-1205)
- Yu Cheng (ORCID: https://orcid.org/0000-0002-3816-3417)
- Lei Pan
- Liyuan Gong
- Zhen Fan (ORCID: https://orcid.org/0000-0001-6813-5743)
- Youli Xiao (ORCID: https://orcid.org/0000-0002-4803-3333)
- Shahzad Toufeeq
- Xuefei Wei
- Bin Li (ORCID: https://orcid.org/0009-0008-3791-0936)
- Ying Zhang (ORCID: https://orcid.org/0000-0002-8526-9636)
- Jihoon Lee (ORCID: https://orcid.org/0000-0001-5327-824X)
- Jun Zhang (ORCID: https://orcid.org/0000-0002-2267-0182)
- Won‐Jae Lee (ORCID: https://orcid.org/0000-0002-1438-8005)
- Wuren Huang (ORCID: https://orcid.org/0000-0001-7193-3201)
- Jingfeng Yang (ORCID: https://orcid.org/0000-0003-1524-0712)
- Rongbing Chen (ORCID: https://orcid.org/0009-0004-2621-2711)
- Yining Liu (ORCID: https://orcid.org/0009-0006-4631-260X)
- Lei Geng (ORCID: https://orcid.org/0000-0003-3471-1890)
Institutions
- Seoul National University (KR)
- Hunan Normal University (CN)
- Shanghai Jiao Tong University (CN)
- Missouri College (US)
- Institut Pasteur of Shanghai (CN)
- Center for Excellence in Molecular Plant Sciences (CN)
- University of Missouri (US)
- Nanjing Medical University (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-08-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116126
- Citations
- 2
- Primary Topic
- Polyamine Metabolism and Applications
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- National Natural Science Foundation of China