代谢物介导的生物大分子动态修饰在肿瘤转移中的作用及调控机制

本项目的研究内容对应重大研究计划重点资助研究方向“（二）生物大分子动态修饰的调控机制及功能解析” ，并重点研究“生物大分子化学修饰在生理过程和病理变化中的调控机制”。代谢异常普遍存在于肿瘤细胞中，并在肿瘤发生发展中发挥至关重要的作用，但其如何调控肿瘤转移却知之甚少。申请人在预实验中发现泛素化修饰可动态调控丝氨酸合成及一碳代谢，并通过改变其代谢产物S-腺苷甲硫氨酸（SAM）的含量动态调控组蛋白甲基化修饰，进而促进肿瘤转移。本项目将在预实验的基础上，继续围绕丝氨酸合成及一碳代谢重编程在肿瘤转移中的作用机制，从三个方面展开研究：1）泛素化介导的丝氨酸合成及一碳代谢重编程机制；2）丝氨酸合成及一碳代谢重编程促进肿瘤细胞迁移的分子机制；3）SAM介导的表观遗传调控的特异性机制。研究结果不仅将揭示SAM介导的组蛋白甲基化修饰在肿瘤转移中的作用及调控机制，还将为肠癌转移提供全新的诊疗策略。

Deregulated metabolism commonly exists in cancer cells and plays the crucial role in cancer progression, while how it contributes to tumor metastasis remains largely unknown. In the preliminary data, the applicant found that ubiquitination can regulate de novo serine synthesis and one-carbon metabolism, through which it alters the levels of S-adenosylmethionine (SAM) and regulates the dynamic histone methylation, thereby promoting tumor metastasis. Basing on these observations, this project will focus on the molecular mechanism, by which the rewired serine synthesis and one-carbon metabolism promote tumor metastasis, and demonstrate 1) the mechanism of ubiquitination-dependent reprogramming of serine synthesis and one-carbon metabolism; 2) the mechanism of rewired serine synthesis and one-carbon metabolism-promoted tumor cell migration; 3) the specificity mechanism of SAM-mediated epigenetic regulation. These findings will not only elaborate the role and regulatory mechanism of SAM-mediated histone methylation in tumor metastasis, but also provide a new strategy for the prognosis and treatment of metastatic colorectal cancer.