FBW7/GSK3β mediated degradation of IGF2BP2 inhibits IGF2BP2-SLC7A5 positive feedback loop and radioresistance in lung cancer

作者：Zhiyuan Zhou, Bin Zhang, Yue Deng, Suke Deng, Jie Li, Wenwen Wei, Yijun Wang, Jiacheng Wang, Zishan Feng, Mengjie Che, Yang Xiao, Jingshu Meng, Yan Li, Yan Hu, Yajie Sun, Lu Wen, Fang Huang, Yuhan Sheng, Chao Wan, Kunyu Yang · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2024 · DOI：10.1186/s13046-024-02959-3 · 被引用次数：28 · 研究领域：Folate and B Vitamins Research、Cancer-related Molecular Pathways、RNA modifications and cancer

Abstract Background The development of radioresistance seriously hinders the efficacy of radiotherapy in lung cancer. However, the underlying mechanisms by which radioresistance occurs are still incompletely understood. The N 6 -Methyladenosine (m 6 A) modification of RNA is involved in cancer progression, but its role in lung cancer radioresistance remains elusive. This study aimed to identify m 6 A regulators involved in lung cancer radiosensitivity and further explore the underlying mechanisms to identify therapeutic targets to overcome lung cancer radioresistance. Methods Bioinformatic mining was used to identify the m 6 A regulator IGF2BP2 involved in lung cancer radiosensitivity. Transcriptome sequencing was used to explore the downstream factors. Clonogenic survival assays, neutral comet assays, Rad51 foci formation assays, and Annexin V/propidium iodide assays were used to determine the significance of FBW7/IGF2BP2/SLC7A5 axis in lung cancer radioresistance. Chromatin immunoprecipitation (ChIP)-qPCR analyses, RNA immunoprecipitation (RIP) and methylated RNA immunoprecipitation (MeRIP)-qPCR analyses, RNA pull-down analyses, co-immunoprecipitation analyses, and ubiquitination assays were used to determine the feedback loop between IGF2BP2 and SLC7A5 and the regulatory effect of FBW7/GSK3β on IGF2BP2. Mice models and tissue microarrays were used to verify the effects in vivo. Results We identified IGF2BP2, an m 6 A “reader”, that is overexpressed in lung cancer and facil...