RBM47类泛素化通过YTHDF2调控m6A修饰促进乳腺癌转移的机制研究

RNA的m6A甲基化修饰与癌症的EMT、CSC和转移关系密切，但具体调控机制还不明确。RBM47是潜在的抑癌基因，基因缺失与EMT、CSC及乳腺癌不良预后和转移正相关，但作为RNA结合蛋白，其蛋白功能改变是否参与调控尚未明确。本课题组前期发现RBM47蛋白二聚体化和乳腺癌侵袭转移密切相关，IP、质谱分析和酵母双杂验证RBM47与m6A的阅读器YTHDF2存在相互作用。还鉴定出HERC5类泛素化修饰RBM47促进其二聚体化，削弱RBM47和YTHDF2相互作用，促进EMT、CSC形成和肿瘤侵袭。因此，提出假设：RBM47通过HERC5介导自身类泛素化和二聚体形成，改变自身与m6A阅读器YTHDF2的相互作用，影响其识别、结合和降解m6A修饰的RNA的能力，从而介导EMT和CSC形成，最终促进肿瘤侵袭转移。本研究的完成对深入了解乳腺癌侵袭转移的分子机制有重要理论意义，同时为治疗提供新靶点。

The m6A methylation modification of RNA is closely related to EMT、CSC and metastasis in cancer, but the specific regulation mechanism is not clear. RBM47 is a potential tumor suppressor gene. Gene deletion of RBM47 is associated with CSC, EMT, poor prognosis and metastasis of breast cancer. However, as a RNA-binding protein, it is not clear whether protein function alteration of RBM47 is involved in biological regulation and regulatory pathways. We previously found that RBM47 dimerization correlated with invasion and metastasis of breast cancer，and verified that RBM47 interacted with m6A reader——YTHDF2 by IP, mass spectrometry and yeast double hybrid. We also found that HERC5 ubiquitination-like modified RBM47 and promoted RBM47 dimerization, contributed to weakening interaction between RBM47 and YTHDF2, and promoted EMT、CSC formation and tumor invasion. Therefore, we propose the hypothesis that: RBM47 mediates dimer formation through ubiquitination-like modifications by HERC5, alters the interaction with m6A reader——YTHDF2, affects its ability to recognize, bind, and degrade m6A-modified RNA, thereby mediating EMT and CSC formation and ultimately promoting tumor invasion and metastasis. The completion of this study has important theoretical significance for understanding the molecular mechanisms of breast cancer invasion and metastasis, and at the same time provides new targets for breast cancer treatment.