Avenanthramide A potentiates Bim-mediated antineoplastic properties of 5-fluorouracil via targeting KDM4C/MIR17HG/GSK-3β 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 adva...
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Elsevier
2024-12-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383524002922 |
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| author | Rong Fu Zhangfeng Dou Ning Li Xueyuan Fan Sajid Amin Jinqi Zhang Yuqing Wang Zongwei Li Zhuoyu Li Peng Yang |
| author_facet | Rong Fu Zhangfeng Dou Ning Li Xueyuan Fan Sajid Amin Jinqi Zhang Yuqing Wang Zongwei Li Zhuoyu Li Peng Yang |
| author_sort | Rong Fu |
| collection | DOAJ |
| description | 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 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 ApcMin/+ 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. |
| format | Article |
| id | doaj-art-0473951a01cd4d93acb4b242f3acf2e5 |
| institution | Kabale University |
| issn | 2211-3835 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
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| series | Acta Pharmaceutica Sinica B |
| spelling | doaj-art-0473951a01cd4d93acb4b242f3acf2e52024-12-18T08:48:42ZengElsevierActa Pharmaceutica Sinica B2211-38352024-12-01141253215340Avenanthramide A potentiates Bim-mediated antineoplastic properties of 5-fluorouracil via targeting KDM4C/MIR17HG/GSK-3β negative feedback loop in colorectal cancerRong Fu0Zhangfeng Dou1Ning Li2Xueyuan Fan3Sajid Amin4Jinqi Zhang5Yuqing Wang6Zongwei Li7Zhuoyu Li8Peng Yang9School of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001, China; Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, ChinaDepartment of Gastroenterology, First Hospital of Shanxi Medical University, Taiyuan 030001, ChinaDepartment of Gastroenterology, First Hospital of Shanxi Medical University, Taiyuan 030001, ChinaSchool of Life Science, Shanxi University, Taiyuan 030006, ChinaDepartment of Precision Medicine, University of Campania Luigi Vanvitelli, Naples 80138, ItalyInstitute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, ChinaInstitute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, ChinaSchool of Life Science, Anhui Medical University, Hefei 230032, China; Corresponding authors.Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China; Corresponding authors.Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China; Corresponding authors.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 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 ApcMin/+ 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.http://www.sciencedirect.com/science/article/pii/S2211383524002922Avenanthramide A5-FluorouracilKDM4CColorectal cancerMIR17HG |
| spellingShingle | Rong Fu Zhangfeng Dou Ning Li Xueyuan Fan Sajid Amin Jinqi Zhang Yuqing Wang Zongwei Li Zhuoyu Li Peng Yang Avenanthramide A potentiates Bim-mediated antineoplastic properties of 5-fluorouracil via targeting KDM4C/MIR17HG/GSK-3β negative feedback loop in colorectal cancer Acta Pharmaceutica Sinica B Avenanthramide A 5-Fluorouracil KDM4C Colorectal cancer MIR17HG |
| title | Avenanthramide A potentiates Bim-mediated antineoplastic properties of 5-fluorouracil via targeting KDM4C/MIR17HG/GSK-3β negative feedback loop in colorectal cancer |
| title_full | Avenanthramide A potentiates Bim-mediated antineoplastic properties of 5-fluorouracil via targeting KDM4C/MIR17HG/GSK-3β negative feedback loop in colorectal cancer |
| title_fullStr | Avenanthramide A potentiates Bim-mediated antineoplastic properties of 5-fluorouracil via targeting KDM4C/MIR17HG/GSK-3β negative feedback loop in colorectal cancer |
| title_full_unstemmed | Avenanthramide A potentiates Bim-mediated antineoplastic properties of 5-fluorouracil via targeting KDM4C/MIR17HG/GSK-3β negative feedback loop in colorectal cancer |
| title_short | Avenanthramide A potentiates Bim-mediated antineoplastic properties of 5-fluorouracil via targeting KDM4C/MIR17HG/GSK-3β negative feedback loop in colorectal cancer |
| title_sort | avenanthramide a potentiates bim mediated antineoplastic properties of 5 fluorouracil via targeting kdm4c mir17hg gsk 3β negative feedback loop in colorectal cancer |
| topic | Avenanthramide A 5-Fluorouracil KDM4C Colorectal cancer MIR17HG |
| url | http://www.sciencedirect.com/science/article/pii/S2211383524002922 |
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