Geng, L., Fan, Z., Chen, R., Cho, K.C., Liu, Y., Cheng, Y., Yang, J., Zhang, Y., Wei, X., Gong, L., Tang, Y., Xu, Z., Huang, W., Toufeeq, S., Zhai, Z., Pan, L., Zhang, J., Li, B., Beerntsen, B.T., Lee, J.H., Xiao, Y., Na, Y., Lee, W.J., Ling, E. (2025). The Nα-acetyl-L-lysine/Loxl2/H2O2 promotes intestinal tumor growth in Drosophila and cell proliferation in human colorectal cancer.  Cell Rep. 44(8): 116126.

FBrf0263279

Research paper

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.