Quercetin Induces Apoptosis in HepG2 Cells via Directly Interacting with YY1 to Disrupt YY1-p53 Interaction

Quercetin is a flavonol found in edible plants and possesses a significant anticancer activity. This study explored the mechanism by which quercetin prevented liver cancer via inducing apoptosis in HepG2 cells. Quercetin induced cell proliferation and apoptosis through inhibiting YY1 and facilitating p53 expression and subsequently increasing the Bax/Bcl-2 ratio. The results revealed that YY1 knockdown promoted apoptosis, whilst YY1 overexpression suppressed apoptosis via direct physical interaction between YY1 and p53 to regulate the p53 signaling pathway. Molecular docking using native and mutant YY1 proteins showed that quercetin could interact directly with YY1, and the binding of quercetin to YY1 significantly decreased the docking energy of YY1 with p53 protein. The interactions between quercetin and YY1 protein included direct binding and non-bonded indirect interactions, as confirmed by cellular thermal shift assay, UV-Vis absorption spectroscopy, fluorescence spectroscopy and circular dichroism spectroscopy. It was likely that quercetin directly bound to YY1 protein to compete with p53 for the binding sites of YY1 to disrupt the YY1-p53 interaction, thereby promoting p53 activation. This study provides insights into the mechanism underlying quercetin’s anticancer action and supports the development of quercetin as an anticancer therapeutic agent.