NSF mediates CDC5L nuclear import to promote cell growth and metastasis in hepatocellular carcinoma

Abstract Intracellular transportation (IT) is dysregulated in tumors. Here, we identified N -ethylmaleimide-sensitive factor (NSF) as one of the IT-associated genes with upregulated expression in hepatocellular carcinoma (HCC). Furthermore, NSF expression is associated with malignant features and poor outcomes of HCC patients. NSF acts as an oncogenic driver that promotes HCC cell viability and metastasis by physically interacting with cell division cycle 5-like protein (CDC5L) and facilitating its nuclear accumulation in a vesicle-independent manner. In the nucleus, CDC5L transcriptionally activates CDK2-associated cullin 1 (CACUL1) expression via occupation of its promoter element. Thus, our findings provide novel insights into the mechanisms underlying the NSF-induced promotion of HCC progression and suggest potential therapeutic targets in the NSF-CDC5L-CACUL1 axis for HCC therapeutics.