FOXD1 activates KIFC1 to modulate aerobic glycolysis and reinforce cisplatin resistance of breast cancer.

BACKGROUND

Breast cancer (BC) is the most prevalent invasive malignant tumor. Cisplatin (DDP) is a prototype of platinum-based chemotherapy drugs, its resistance severely hinders its clinical application. This project intended to figure out the exact mechanism of KIFC1 in the DDP resistance of BC.

METHODS

The levels of KIFC1 and FOXD1 in BC as well as their binding sites were investigated by bioinformatics analysis. The signaling pathways regulated by FOXD1 were analyzed. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays verified the binding relationship between the two. Through quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB), we assessed the expression of FOXD1, KIFC1, and glycolysis-related genes. CCK-8 assay was applied in the determination of cell viability to assess the efficacy of DDP resistance. Extracellular acidification rate (ECAR), glucose consumption, lactate synthesis, Adenosine triphosphate (ATP) content, and oxygen consumption rate (OCR) were measured to evaluate glycolysis.

RESULTS

FOXD1 and KIFC1 were significantly upregulated in BC, with KIFC1 being significantly enriched in the glycolysis pathway. Overexpression of KIFC1 significantly enhanced the DDP resistance of BC cells, while promoting aerobic glycolysis. Mechanistically, FOXD1 was bound to the promoter of KIFC1 to activate its transcription. Its overexpression counteracted the inhibitory effect of KIFC1 knockdown on the DDP resistance of BC cells.

CONCLUSION

FOXD1 activates the glycolysis pathway by upregulating KIFC1, thereby facilitating BC cells' DDP resistance. Therefore, the FOXD1/KIFC1 axis linked the glycolysis pathway to DDP resistance and may be a promising new target for reinforcing DDP resistance in BC.