磷酸化修饰调控SET1A活性及其在肿瘤中的机制及功能研究

SET1A is the major H3K4me3 methyltransferase, it regulates the heterochromatin formation and gene transcription regulation, and its dysfunction is closely related to cancer. However, the key role and molecular mechanism of SET1A in tumorigenesis and development are not very clear. Therefore, the signal transduction pathway and molecular mechanism of SET1A regulation are very important for the prevention and treatment of tumor. Our previous studies found that SET1A promotes the tumorigenesis by methylating the core downstream factor YAP of Hippo signaling pathway. Here, we show that extracellular signal factor may be involved in the regulation of SET1A methyltransferase activity and there are two potential AKT phosphorylation sites in SET1A, indicating that extracellular signal may regulate the function of SET1A through phosphorylation. We also found that SET1A significantly promoted tumorigenesis in animal functional experiments and clinical pathological microarray analysis. Based on these findings, we plan to clarify detailed mechanism and biological function of extracellular signal regulating phosphorylation of SET1A and epigenetic regulation involved in colorectal tumorigenesis and development , and to prove a potential target on SET1A in clinic drug development.

SET1A是主要的H3K4me3甲基转移酶，影响异染色质形成和基因转录调控，其功能异常与癌症密切相关。但SET1A在肿瘤发生发展各阶段所起的关键作用及分子机制仍然未知。因此，解析调控SET1A活性的信号转导通路及分子机制，对肿瘤防治至关重要。我们前期研究发现SET1A甲基化Hippo信号下游因子YAP，促进肿瘤发生。同时，多种胞外信号调控SET1A甲基转移酶活性，并且发现SET1A存在两个AKT磷酸化位点，提示胞外信号可能通过磷酸化修饰调控SET1A功能。此外，我们还在动物和临床分析中发现SET1A明显促进细胞增殖和肿瘤发生。本项目将以此为基础，以结直肠癌为研究主体，从肿瘤微环境因子介导SET1A磷酸化修饰入手，分别在细胞、动物和病理样本水平研究胞外信号通过特定信号转导通路介导磷酸化修饰调控SET1A活性和表观修饰，调节肿瘤发生发展的分子机制及生物学功能，为开发SET1A药物提供靶点。

SET1A是主要的H3K4me3甲基转移酶，影响异染色质形成和基因转录调控，其功能异常与癌症密切相关。但是SET1A在肿瘤发生发展各阶段所起的关键作用及分子机制仍然未知。因此，解析调控SET1A活性的信号转导通路及分子机制，对肿瘤防治至关重要。我们前期研究发现SET1A甲基化Hippo信号下游因子YAP，促进肿瘤发生。同时，多种胞外信号调控SET1A甲基转移酶活性，并且发现SET1A存在两个AKT磷酸化位点，提示胞外信号可能通过磷酸化修饰调控SET1A功能。此外，我们还在动物和临床分析中发现SET1A明显促进细胞增殖和肿瘤发生。本项目以此为基础，通过深入研究取得了研究进展包括：1）确定磷酸化修饰调控SET1A的甲基转移酶活性；2）阐明了甲基转移酶SET1A作为重要表观调控因子调节肿瘤相关巨噬细胞表观重编程和代谢重编程交互调控的作用机制，并发现肿瘤相关微生物组影响肿瘤相关巨噬细胞表观修饰水平；3）发现巨噬细胞特异性敲除甲基转移酶SET1A明显促进肿瘤生长，促进肿瘤相关巨噬细胞的免疫浸润增强和CD8+ T细胞的免疫浸润减少。本项目系统解析了肿瘤细胞和巨噬细胞中甲基转移酶SET1A的不同功能及调控机制，发现SET1A在肿瘤进展中的作用可能是一把双刃剑，提出靶向SET1A的精准治疗是肿瘤治疗的潜在靶点。