G-CSF promotes H3K27ac-modified KLF5 to activate CXCR4 expression and drive colon cancer growth and metastasis.

[OBJECTIVE] This study investigated how granulocyte colony-stimulating factor (G-CSF) regulates colon cancer (CC) progression through epigenetic activation of the kruppel-like factor 5 (KLF5)/chemokine receptor type 4 (CXCR4) axis.

[METHODS] Human CC LoVo cells were exposed to G-CSF (20 ng/mL) alone in combination with si-KLF5, oe-CXCR4, or the CXCR4 antagonist AMD3100 for 24 h. Malignant behaviors were evaluated by CCK-8, colony formation, and Transwell assays. H3K27ac modification on the KLF5 promoter and KLF5 binding to the CXCR4 promoter were examined using immunofluorescence, dual-luciferase reporter, and ChIP assays. An orthotopic LoVo xenograft mouse model was used to assess tumor growth, metastasis, and epithelial-mesenchymal transition (EMT) marker expression. KLF5 and CXCR4 mRNA and protein levels were measured in CC cells and tissues via RT-qPCR and western blot.

[RESULTS] G-CSF enhanced LoVo cell proliferation, migration, and invasion in a dose-dependent manner, concomitant with increased H3 acetylation and histone H3 lysine 27 (H3K27ac) acetylation. Mechanistically, G-CSF upregulated KLF5 expression via H3K27ac modification, promoting CXCR4 transcriptional activation. Inhibition of KLF5 or CXCR4 partially reversed G-CSF-induced EMT and malignant phenotypes. In vivo, G-CSF accelerated tumor growth and metastasis through the KLF5/CXCR4 signaling pathway, confirming its pro-tumorigenic role.

[CONCLUSIONS] G-CSF drives CC progression by enhancing H3K27ac-dependent upregulation of KLF5, which transactivates CXCR4 to promote EMT, proliferation and metastasis. Targeting the G-CSF/KLF5/CXCR4 axis may represent a potential therapeutic strategy for advanced CC.