Chemoresistance to 5-fluorouracil(5-FU)is a significant challenge in treating colorectal can-cer(CRC).Novel combined regimens to thwart chemoresistance are therefore urgently needed.Herein,we demonstrated that the com...Chemoresistance to 5-fluorouracil(5-FU)is a significant challenge in treating colorectal can-cer(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 therapeu-tic 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 MIR17HG promoter to block its transcription and derepress Bim expression.AVN A enhanced the therapeutic efficacy of 5-FU via impairing the KDM4C/MIR17HG/GSK-3β negative feedback loop.Importantly,the clinical correlation of the KDM4C/MIR17HG/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 Apc ^(Min/+)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/MIR17HG/GSK-3β negative feedback loop which confers therapeutically exploitable vulnerability to chemo-refractory CRC patients.展开更多
基金supported by the National Natural Science Foundation of China(Nos.32200321,82270217,31800657,32072220)National Natural Science Foundation of China Regional Innovation and Development Joint Fund Key Support Project(U23A20526,China)+1 种基金Natural Science Foundation of Shanxi Province(Nos.20210302124252,and 202203021211293,China),Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi(2021L212,China)“1331 Project”Key Innovation Team of Shanxi Province(Prof.Zhuoyu Li).
文摘Chemoresistance to 5-fluorouracil(5-FU)is a significant challenge in treating colorectal can-cer(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 therapeu-tic 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 MIR17HG promoter to block its transcription and derepress Bim expression.AVN A enhanced the therapeutic efficacy of 5-FU via impairing the KDM4C/MIR17HG/GSK-3β negative feedback loop.Importantly,the clinical correlation of the KDM4C/MIR17HG/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 Apc ^(Min/+)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/MIR17HG/GSK-3β negative feedback loop which confers therapeutically exploitable vulnerability to chemo-refractory CRC patients.
