Abstract

Treatment options for hepatocellular carcinoma (HCC) remain limited, and patient prognosis is generally poor. Therefore, elucidating the molecular mechanisms underlying HCC initiation and progression is critical for identifying novel therapeutic targets. Our previous study demonstrated that BICD cargo adaptor 1 (BICD1) was upregulated in HCC and functioned as a tumor promoter. However, the upstream regulators of BICD1 expression and the molecular basis of its pro-tumorigenic effects remain unclear. In this study, we identified Yes-associated protein (YAP) as a positive regulator of BICD1 in HCC. Mechanistically, YAP directly bound to the BICD1 promoter and enhanced its transcriptional activity. BICD1 expression was positively correlated with YAP, connective tissue growth factor (CTGF), and cysteine-rich angiogenic inducer 61 (CYR61) in HCC tissues. Functionally, BICD1 knockdown significantly attenuated hypoxia-induced proliferation, sphere formation, and migration of HCC cells, whereas BICD1 overexpression enhanced these phenotypes. In addition, BICD1 depletion markedly suppressed tumor initiation and growth in a nude mouse model. Further mechanistic investigations revealed that BICD1 interacted with hypoxia-inducible factor-1α (HIF-1α) via its C-terminal CC3 domain, thereby promoting HIF-1α nuclear translocation and transcriptional activity in HCC cells. Notably, AKT activation or knockdown of glycogen synthase kinase 3β (GSK3β) significantly enhanced the interaction between BICD1 and HIF-1α, thereby increasing HIF-1α transcriptional activity. Collectively, these findings demonstrate that YAP-driven BICD1 expression facilitates HIF-1α nuclear translocation and activation of downstream target genes, thereby promoting hypoxia-induced proliferation, stemness, and migration in HCC. This study highlights the YAP–BICD1–HIF-1α axis as a potential therapeutic target in HCC. Download: Download high-res image (122KB) Download: Download full-size image