Circular RNA KIF4A Promotes Liver Metastasis of Breast Cancer by Reprogramming Glucose Metabolism

BACKGROUND: Circular RNAs (circRNAs) regulate complex functional processes and play crucial roles in cancer development and progression. It was reported that circKIF4 regulates the progression of triple-negative breast cancer (TNBC). This study evaluates the role of circKIF4 in breast cancer distant metastasis and metabolic reprogramming. METHODS: RT-qPCR was performed to verify the expression of circKIF4A in breast cancer, liver metastatic tissues, and cell lines. The function of circKIF4A in metastasis was evaluated both in vitro and in vivo through a series of experiments, including cell migration and glucose intake experiments. Additionally, we conducted molecular experiments to clarify the regulatory role of circKIF4A. We then conducted a Luciferase reporter assay and an RNA immunoprecipitation assay to identify the molecular interactions between circKIF4A and miRNA. RESULTS: circKIF4A was overexpressed in breast cancer cell lines and tissues, inhibiting its expression and suppressing breast cancer growth and metastasis. Interestingly, we observed that circKIF4A reprogrammed the glucose metabolism of breast cancer, and silencing circKIF4A greatly affected glucose uptake and lactate production in breast cancer cells. miR-335 can be sponged by circKIF4A, which affected the expression of ALDOA/OCT4 protein and regulated HK2/PKM2 expression. CONCLUSIONS: This study demonstrated that the circKIF4A-miR-335-OCT4/ALDOA-HK2/PKM2 axis is critical to breast cancer metabolic reprogramming, indicating that this axis could be a novel therapeutic target for the treatment of liver metastasis of breast cancer.