Avenanthramide A potentiates Bim-mediated antineoplastic properties of 5-fluorouracil targeting KDM4C//GSK-3 negative feedback loop in colorectal cancer.

Chemoresistance to 5-fluorouracil (5-FU) is a significant challenge in treating colorectal cancer (CRC). Novel combined regimens to thwart chemoresistance are therefore urgently needed. Herein, we demonstrated that the combination of Avenanthramide A (AVN A) and 5-FU has significant therapeutic advantages against CRC. Mechanistically, AVN A directly binds to the S198 site of the histone lysine demethylase KDM4C to promote its degradation, which subsequently fosters H3K9me3 occupancy on the promoter to block its transcription and derepress Bim expression. AVN A enhanced the therapeutic efficacy of 5-FU impairing the KDM4C//GSK-3 negative feedback loop. Importantly, the clinical correlation of the KDM4C//Bim signaling axis with 5-FU response was validated in the refractory CRC patients. We provide evidence for the enhanced effectiveness of 5-FU when combined with AVN A in chemoresistant xenografts, CRC organoids, and mouse model. Additionally, AVN A mitigated the systemic adverse effects of 5-FU. Overall, our findings demonstrate that combinatorial therapy with AVN A and 5-FU represents an appealing opportunity and highlights KDM4C//GSK-3 negative feedback loop which confers therapeutically exploitable vulnerability to chemo-refractory CRC patients.