Fusobacterium Nucleatum Promotes the Development of Colorectal Cancer by Activating a Cytochrome P450/Epoxyoctadecenoic Acid Axis via TLR4/Keap1/NRF2 Signaling

Cancer Res. 2021 Sep 1;81(17):4485-4498. doi: 10.1158/0008-5472.CAN-21-0453. Epub 2021 Jun 23.


Emerging research has revealed regulation of colorectal cancer metabolism by bacteria. Fusobacterium nucleatum (Fn) plays a crucial role in the development of colorectal cancer, however, whether Fn infection modifies metabolism in patients with colorectal cancer remains unknown. Here, LC-MS/MS-based lipidomics identified the upregulation of cytochrome P450 monooxygenases, primarily CYP2J2, and their mediated product 12,13-EpOME in patients with colorectal cancer tumors and mouse models, which increased the invasive and migratory ability of colorectal cancer cells in vivo and in vitro by regulating the epithelial-mesenchymal transition (EMT). Metagenomic sequencing indicated a positive correlation between increased levels of fecal Fn and serum 12,13-EpOME in patients with colorectal cancer. High levels of CYP2J2 in tumor tissues also correlated with high Fn levels and worse overall survival in patients with stage III/IV colorectal cancer. Moreover, Fn was found to activate TLR4/AKT signaling, downregulating Keap1 and increasing NRF2 to promote transcription of CYP2J2. Collectively, these data identify that Fn promotes EMT and metastasis in colorectal cancer by activating a TLR4/Keap1/NRF2 axis to increase CYP2J2 and 12,13-EpOME, which could serve as clinical biomarkers and therapeutic targets for Fn-infected patients with colorectal cancer. SIGNIFICANCE: This study uncovers a mechanism by which Fusobacterium nucleatum regulates colorectal cancer metabolism to drive metastasis, suggesting the potential biomarker and therapeutic utility of the CYP2J2/12,13-EpOME axis in Fn-infected patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Carcinogenesis
  • Cell Line, Tumor
  • Cell Movement
  • Colorectal Neoplasms / complications
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / microbiology
  • Cytochrome P-450 CYP2J2 / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Epithelial-Mesenchymal Transition
  • Female
  • Fusobacterium Infections / complications
  • Fusobacterium Infections / metabolism*
  • Fusobacterium Infections / microbiology
  • Fusobacterium nucleatum / metabolism
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / metabolism*
  • Male
  • Metabolomics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • NF-E2-Related Factor 2 / metabolism*
  • Neoplasm Metastasis
  • Oleic Acids / metabolism*
  • Signal Transduction
  • Toll-Like Receptor 4 / metabolism*


  • 12,13-epoxy-11-hydroxy-9-octadecenoic acid
  • Cyp2j5 protein, mouse
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Oleic Acids
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP2J2