Mechanistic Insights into the FOXM1/BUB1 axis-Mediated Oncogenic Signaling in Hepatocellular Carcinoma

The development of novel therapeutic strategies for advanced and metastatic hepatocellular carcinoma (HCC) remains an urgent clinical need. Despite suboptimal efficacy, the breakthrough of tyrosine kinase inhibitors in HCC treatment therapy underscores the advantage of targeted therapy. Therefore, innovative targeted therapies are urgently needed to enhance treatment efficacy, decrease recurrence rates, and improve patient survival outcomes. The forkhead box M1 (FOXM1) transcription factor serves as a master regulator of oncogenic signaling networks that drive cancer progression. Our study identified budding uninhibited by benzimidazoles 1 (BUB1) as a crucial downstream effector of FOXM1, with demonstrated direct protein-protein interaction. Moreover, FOXM1 directly bound to the GTAAACC motif at the -293 bp region of the BUB1 promoter and activated its transcription, thereby driving HCC cell proliferation. Mechanism studies have shown that the FOXM1/BUB1 axis regulated multiple oncogenic processes in HCC, including cell proliferation, DNA repair, G2/M cell cycle transition, stemness, invasion, and migration. Knockdown of BUB1 significantly sensitized HCC cells and xenograft tumors to the FOXM1 inhibitor FDI-6. Furthermore, combined pharmacological inhibition of FOXM1 (FDI-6, RCM-1, thiostrepton) and BUB1 (BAY-1816032) synergistically inhibited the proliferation of HCC cells and xenograft tumors. These findings establish FOXM1-mediated BUB1 upregulation as a key driver of HCC malignancy. Targeting the FOXM1/BUB1 axis represents a promising therapeutic strategy for the treatment of advanced and metastatic HCC, offering new opportunities for HCC therapy.