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

Haitao Gao; Jing Wang; Jiacai Liu; Huihua Wang; Tiantian Wang; Sha Li; Lili Niu; Ya Wei

doi:10.1016/j.repbio.2024.100969

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

Reprod Biol. 2024 Nov 13;25(1):100969. doi: 10.1016/j.repbio.2024.100969. Online ahead of print.

Authors

Haitao Gao¹, Jing Wang¹, Jiacai Liu¹, Huihua Wang¹, Tiantian Wang¹, Sha Li¹, Lili Niu¹, Ya Wei²

Affiliations

¹ General Surgery Department, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, China.
² General Surgery Department, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, China. Electronic address: wiweiya@163.com.

PMID: 39541848
DOI: 10.1016/j.repbio.2024.100969

Abstract

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.

Keywords: Aerobic glycolysis; Breast cancer; Cisplatin resistance; FOXD1; KIFC1.