Avenanthramide A potentiates Bim-mediated antineoplastic properties of 5-fluorouracil via targeting KDM4C/MIR17HG/GSK-3β negative feedback loop in colorectal cancer.
10.1016/j.apsb.2024.07.018
- Author:
Rong FU
1
;
Zhangfeng DOU
2
;
Ning LI
2
;
Xueyuan FAN
3
;
Sajid AMIN
4
;
Jinqi ZHANG
5
;
Yuqing WANG
5
;
Zongwei LI
6
;
Zhuoyu LI
5
;
Peng YANG
5
Author Information
1. School of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001, China.
2. Department of Gastroenterology, First Hospital of Shanxi Medical University, Taiyuan 030001, China.
3. School of Life Science, Shanxi University, Taiyuan 030006, China.
4. Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples 80138, Italy.
5. Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China.
6. School of Life Science, Anhui Medical University, Hefei 230032, China.
- Publication Type:Journal Article
- Keywords:
5-Fluorouracil;
Avenanthramide A;
Colorectal cancer;
KDM4C;
MIR17HG
- From:
Acta Pharmaceutica Sinica B
2024;14(12):5321-5340
- CountryChina
- Language:English
-
Abstract:
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 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.
