4-Hydroxychalcone Exert the Anti-cancer Potential in Colorectal Cancer Through Targeting CDK6

BACKGROUND: Colorectal cancer (CRC) is a prevalent and highly lethal malignancy characterized by frequent recurrence and high mortality. 4-Hydroxychalcone (4HC), a common chalcone abundant in daily foods, exhibits multiple biomedical properties, notably anticancer activities. However, the role of 4HC in CRC remains unclear. METHODS: Cell proliferation was assessed using cell counting and colony formation assays. Two patient-derived organoid models of CRC and a subcutaneous xenograft model in nude mice treated with 4HC were established to evaluate tumor growth in vivo. Cell cycle distribution, intracellular reactive oxygen species (ROS), DNA damage, and cell senescence were analyzed by flow cytometry, comet assay, SA-β-Gal staining, and western blotting. Molecular docking, cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) were performed to determine the interaction between 4HC and CDK6. CDK6 expression in CRC was examined using the TCGA-COAD bulk sequencing dataset and CRC tissue microarrays via immunohistochemistry. RESULTS: We systematically demonstrated that 4HC exerts anticancer effects both in vitro and in vivo. Additionally, 4HC induced cell cycle arrest, promoted ROS accumulation, and triggered DNA damage and cellular senescence in CRC cells. Mechanistically, 4HC exhibited strong binding affinity to CDK6. Furthermore, CDK6 expression was elevated in CRC tissues. Inhibition of CDK6 suppressed cell proliferation, increased ROS production, and induced senescence in CRC cells, whereas the efficacy of 4HC was significantly diminished upon CDK6 silencing. CONCLUSION: This study demonstrates that 4HC acts as a CDK6 inhibitor, exhibiting potent anticancer effects, and provides a potential novel therapeutic strategy for CRC.