放射治疗是肺癌治疗的重要手段，而放疗抵抗是影响肺癌疗效最主要的因素之一。组蛋白去甲基化酶KDM4C能调控DNA双链断裂修复，影响基因组稳定性，但其在肺癌放疗抵抗中的作用及调控机制尚不明确。本课题组前期研究显示：KDM4C在肺癌细胞系中高表达并促进肺癌细胞放疗抵抗。运用成熟的串联亲和纯化/质谱技术及免疫共沉淀实验发现E3泛素连接酶FBXO22是KDM4C相互作用蛋白，且FBXO22可负向调控KDM4C蛋白稳定性并增强肺癌细胞放疗敏感性，提示KDM4C可能是FBXO22的泛素化底物分子。结合以上预实验结果我们推测：FBXO22通过与KDM4C结合并促进其泛素化降解，抑制KDM4C去甲基化酶活性及其下游靶基因的表达，进而增强肺癌放疗敏感性。本项目将进一步探索FBXO22调控KDM4C泛素化降解的分子机制，明确FBXO22和KDM4C在肺癌放疗抵抗中的功能及临床意义，为肺癌放射治疗提供新的靶标。

Radiotherapy is the major treatment for lung cancer. Radioresistance is considered the main cause of the failure to cure this cancer. Histone demethylase KDM4C has been reported to be involved in DNA double-strand break repair and genomic stability. However, the role and regulatory mechanism of KDM4C in lung cancer remain unclear. Our preliminary data show that KDM4C protein level is upregulated in lung cancer cell lines and promotes radioresistance of lung cancer cells. Using tandem affinity purification/mass spectrometry and immunoprecipitation methods, our data show FBXO22 interacts with KDM4C and negatively controls its protein stability, suggesting KDM4C may be a ubiquitination substrate of FBXO22. Therefore, the current proposal hypothesizes that E3 ligase FBXO22 binds to and promotes the proteolysis of KDM4C, which then inhibits the activity of histone demethylase KDM4C and the expression of its downstream genes, ultimately enhancing the radiosensitivity in lung cancer. Our proposal aims to explore the underlying mechanisms how FBXO22 negatively controls the degradation of KDM4C and uncover the roles as well as clinical significances of FBXO22 and KDM4C in lung cancer, and may provide novel targets for lung cancer radiotherapy.