Disintegration of the KITENIN/ErbB4 Functional Complex by the Flavonoid Hispidulin Suppresses Colorectal Cancer Progression

Abstract KITENIN (KAI1 C‐terminal interacting tetraspanin, VANGL1) has oncogenic functions and plays a role in the progression of colorectal cancer by interacting with many proteins, including ErbB4, DVL2, RACK1, and KSRP. The receptor tyrosine kinase ErbB4 forms a complex with KITENIN to activate the downstream AP‐1 signaling axis. Therefore, disrupting this oncogenic complex is a promising therapeutic strategy. In this study, the potential therapeutic effects of the flavonoid hispidulin on the KITENIN/ErbB4 oncogenic complex and its signaling are examined. The effects of hispidulin on the KITENIN/ErbB4 oncogenic complex and colorectal cancer progression are evaluated by in vitro and in silico studies, including the investigation of oncometabolite levels. The results show that hispidulin binds to ErbB4 and blocks the interaction between KITENIN and ErbB4, thereby reducing KITENIN‐mediated cell motility, AP‐1 signaling, transcriptional regulator expression, aerobic glycolysis, and levels of metabolites associated with energy metabolism in colorectal cancer. In addition, hispidulin causes the lysosomal degradation of ErbB4 and KITENIN. Hispidulin has a promising therapeutic effect on signaling mediated by the KITENIN/ErbB4 oncogenic complex.