MFN2 inhibits colorectal cancer tumorigenesis by regulating glycolysis through TRIM21-mediated PFKP stability.

Background

Colorectal cancer (CRC) is the third most common gastrointestinal cancer in terms of morbidity and mortality worldwide. Reprogramming of glucose metabolism will directly affect the energy supply pattern of tumor cells and determine their malignant biological behavior. Mitofusin-2 (MFN2) has been shown to be associated with glycolysis. Therefore, targeting MFN2 may be a potential therapeutic approach for CRC.

Methods

Firstly, GSE143939, GSE81558 dataset and GSE184093 dataset were used to screen differentially expressed mRNAs in CRC. The expression of MFN2 in colorectal cancer was detected by TCGA website, Immunohistochemistry and western blot analysis. The impacts of MFN2 on CRC malignant biological behavior were evaluated by a series of in vitro assays. The potential molecular mechanism of MFN2 was elucidated by co-immunoprecipitation, immunofluorescence staining, western blotting and rescue experiment. The effect of MFN2 on tumor growth capacity was assessed in xenograft model.

Results

TCGA and GEO data analysis showed that MFN2 was differentially expressed in CRC, which was significantly lowly expressed in CRC cell lines and tissues. Aberrant expression of MFN2 could reduce glycolysis of CRC cells in vitro and subsequently activate apoptosis and hinder proliferation and migration in vitro. In vivo, MFN2 overexpression retarded tumor growth rate. Mechanistically, MFN2 interacted with PFKP and facilitated the binding of TRIM21 to PFKP to mediate its degradation, thereby hindering the malignant progression of CRC.

Conclusions

Overexpression of MFN2 suppressed CRC cell glycolysis and tumor growth by enhancing TRIM21-mediated degradation of PFKP. Targeting the MFN2/TRIM21/PFKP axis may serve as a new direction for CRC treatment.