ANGPTL4 Facilitates the Persistence of Fusobacterium Nucleatum in Colorectal Cancer

Objectives: Fusobacterium nucleatum is linked to the development, metastasis and chemoresistance of colorectal cancer (CRC). Numerous clinical and animal studies reveals an enrichment of F. nucleatum in the tumor tissue compared with adjacent normal tissue. Nonetheless, the mechanism underlies the colonization and persistence of F. nucleatum in CRC tissue is not fully clarified.
Methods: The mechanism of how F. nucleatum stimulates glycolysis activity of CRC cells and facilities its own colonization was investigated in vitro and confirmed with the Cancer Genome Atlas (TCGA) datasets, clinical tissues, and a xenograft model. The relationship between histone acetylation, ANGPTL4 induction, glycolysis activity of CRC cells and F. nucleatum persistence were further elucidated in vitro and in vivo.
Results: We demonstrated that F. nucleatum infection remarkably promoted glucose uptake and glycolysis activity in CRC cells by elevating the ANGPTL4 expression in vitro and in vivo, which were necessary for the colonization of F. nucleatum itself. Furthermore, overall increased acetylation of histone H3 lysine 27 was observed in F. nucleatum infected CRC cells and clinical tumors, which was specifically responsible for the corresponding transcriptional regulation of ANGPTL4.
Conclusions: This study suggests the metabolic reprogramming of CRC cells is essential for the persistence of F. nucleatum. By interfering ANGPTL4-mediated glycolysis enhancement of CRC cells, the F. nucleatum colonization and its tumor-promoting effects could be eradicated in CRC patients.