FGF19-mediated ELF4 overexpression promotes colorectal cancer metastasis through transactivating FGFR4 and SRC

by Selleckchem | Aug 07 2023

Background: Metastasis accounts for the high lethality of colorectal cancer (CRC) patients. Unfortunately, the molecular mechanism manipulating metastasis in CRC is still elusive. Here, we investigated the function of E74-like factor 4 (ELF4), an ETS family member, in facilitating CRC progression.

Methods: The expression of ELF4 in human CRC samples and CRC cell lines was determined by quantitative real-time PCR, immunohistochemistry and immunoblotting. The migratory and invasive phenotypes of CRC cells were evaluated by in vitro transwell assays and in vivo metastatic models. The RNA sequencing was used to explore the downstream targets of ELF4. The luciferase reporter assays and chromatin immunoprecipitation assays were used to ascertain the transcriptional regulation related to ELF4.

Results: We found elevated ELF4 was positively correlated with distant metastasis, advanced AJCC stages, and dismal outcomes in CRC patients. ELF4 expression was also an independent predictor of poor prognosis. Overexpression of ELF4 boosted CRC metastasis via transactivating its downstream target genes, fibroblast growth factor receptor 4 (FGFR4) and SRC proto-oncogene, non-receptor tyrosine kinase, SRC. Fibroblast growth factor 19 (FGF19) upregulated ELF4 expression through the ERK1/2/SP1 axis. Clinically, ELF4 expression had a positive correlation with FGF19, FGFR4 and SRC, and CRC patients who positively coexpressed FGF19/ELF4, ELF4/FGFR4, or ELF4/SRC exhibited the worst clinical outcomes. Furthermore, the combination of the FGFR4 inhibitor BLU-554 and the SRC inhibitor KX2-391 dramatically suppressed ELF4-mediated CRC metastasis.

Conclusions: We demonstrated the essentiality of ELF4 in the metastatic process of CRC, and targeting the ELF4-relevant positive feedback circuit might represent a novel therapeutic strategy.

Comments:

Summary: In this study, researchers investigated the role of a protein called E74-like factor 4 (ELF4) in colorectal cancer (CRC) metastasis. They found that ELF4 expression was elevated in human CRC samples and cell lines, and its levels were positively correlated with distant metastasis, advanced stages of cancer, and poor outcomes in CRC patients. ELF4 was identified as an independent predictor of poor prognosis.

The researchers discovered that ELF4 promoted CRC metastasis by activating the expression of two target genes: fibroblast growth factor receptor 4 (FGFR4) and SRC proto-oncogene, a non-receptor tyrosine kinase. They also found that fibroblast growth factor 19 (FGF19) upregulated ELF4 expression through the ERK1/2/SP1 axis.

Clinically, the expression of ELF4 was positively correlated with the expression of FGF19, FGFR4, and SRC in CRC patients. Patients who coexpressed FGF19/ELF4, ELF4/FGFR4, or ELF4/SRC had the worst clinical outcomes.

The researchers further tested the combination of an FGFR4 inhibitor (BLU-554) and an SRC inhibitor (KX2-391) and found that it significantly suppressed ELF4-mediated CRC metastasis.

Overall, this study demonstrated the importance of ELF4 in CRC metastasis and suggested that targeting the positive feedback circuit involving ELF4, FGFR4, and SRC could be a potential therapeutic strategy for CRC patients.