NSUN2/EP300正反馈环路调控表观遗传交互对话促进骨肉瘤细胞干性的机制研究

骨肉瘤（OS）是儿童和青少年常见恶性肿瘤，m5C修饰是重要的表观转录调控方式，但在OS中的作用不明。前期研究指出OS中NSUN2高表达，上调干性相关基因mRNA m5C修饰和表达，增强肿瘤干性，促进OS增殖、侵袭和转移，EP300是其主要下游靶点。靶向NSUN2可以阻止OS恶性进展，但其过表达机制尚不明确。申请人发现NSUN2上调EP300 mRNA m5C修饰并促进其表达，而EP300作为组蛋白乙酰转移酶又可以通过组蛋白修饰反馈上调NSUN2的表达。因此，申请人提出假说：在OS中，存在NSUN2/EP300正反馈环路，通过介导mRNA m5C修饰与组蛋白乙酰化之间的交互对话（Cross-talk），彼此激活并维持高表达，最终增强肿瘤干性。本研究拟阐明NSUN2/EP300环路表观遗传调控机制和过程；探索其对肿瘤干性的影响及下游机制；寻找潜在的治疗靶点，为改善OS整体预后提供理论依据。

Osteosarcoma (OS) is a common malignant tumor in children and adolescents. mRNA m5C modification is one of the most important epigenetic regulation mechanisms, but its role in OS remains unknown. Previous studies have pointed out that NSUN2 is highly expressed in OS, which can enhance cancer stemness and promote the proliferation, invasion and metastasis of OS by up-regulating mRNA m5C modifications of related genes, and EP300 is the main downstream target. Targeting NSUN2 leads to obvious anti-tumor effect in OS, but the mechanism of its overexpression is not clear. We found that NSUN2 up-regulated EP300 mRNA m5C modification and promoted its expression, while EP300, as a histone acetyltransferase, could up-regulate the expression of NSUN2 through histone modification feedback. Therefore, We hypothesized that there is a NSUN2/EP300 positive feedback loop in OS, which mediates the interactive cross-talk between mRNA m5C modification and histone acetylation, activates each other and maintains overexpression, and therefore enhances the stemness of OS cells. The purpose of this study is to clarify the epigenetic regulation mechanism and biological process of NSUN2/EP300 positive feedback loop, to explore its effect on OS stemness and its downstream mechanism, and to find potential therapeutic targets for OS. This study provides theoretical basis for improving the overall prognosis of OS.