CLK3 regulates tumor angiogenesis by modulating HIF1α ubiquitination.

Tumor angiogenesis is a critical driver of cancer progression and is regulated by a complex network of signaling pathways. However, limited therapeutic efficacy and the emergence of drug resistance remain significant obstacles, necessitating the exploration of novel angiogenesis inhibitors, alternative pathways, and reliable biomarkers. In this study, we investigate the role of CDC-like kinase 3 (CLK3) in tumor angiogenesis and its underlying molecular mechanisms. Bioinformatic analysis of clinical datasets revealed that CLK3 expression positively correlated with angiogenesis-related pathways in colorectal cancer. In vitro and in vivo experiments confirmed that CLK3 overexpression promoted tumor angiogenesis, whereas CLK3 knockout inhibited this process. Mechanistically, we demonstrated that CLK3 directly interacted with and stabilizes hypoxia-inducible factor 1-alpha (HIF1α) by inhibiting its ubiquitin-proteasome-mediated degradation. Additionally, CLK3 promoted the phosphorylation of HIF1α at tyrosine residues. Furthermore, our functional assays confirmed that CLK3-mediated tumor angiogenesis was dependent on HIF1α. These findings highlight the importance of CLK3 in regulating tumor angiogenesis, and provide compelling evidence for targeting CLK3 as a potential therapeutic strategy for colorectal cancer treatment.