Hypoxia-mediated HES4 promotes the proliferation and motility of hepatocellular carcinoma cell by enhancing COL4A2 transcription.

Hypoxia is a key feature of hepatocellular carcinoma (HCC) tissues. On one hand, it can drive HCC cell to alter their energy metabolism; on the other hand, it promotes the activation of multiple signaling pathways, thereby facilitating the progression of HCC. This study aims to explore the key hypoxia-driven genes and clarify their roles and molecular mechanisms. Through bioinformatics analysis of HCC tissues in the TCGA dataset, we identified 34 genes closely associated with hypoxia in HCC tissues. Among these 34 genes, we found that HES4 was highly expressed in HCC tissues and was associated with poor prognosis in patients. Using CCK-8, EdU assays, wound healing assays, and transwell assays, we demonstrated that knocking down HES4 significantly inhibited the proliferation and motility of HCC cell and notably alleviated hypoxia-induced enhancement of proliferation and motility. Mechanistically, we found that COL4A2 was highly expressed in HCC tissues with high HES4 expression and was positively correlated with HES4 expression. Furthermore, we discovered that HES4 could bind to the promoter of COL4A2 to promote its transcription. Overexpression of COL4A2 could reverse the effects mediated by HES4 silencing. Overall, this study revealed that hypoxia-mediated HES4 promotes the proliferation and motility of HCC cell by enhancing the transcription of COL4A2. HES4 was a key therapeutic target and biomarker in HCC.