染色体重塑因子DPF3在肾细胞癌中的作用及其分子机制研究

Renal cell carcinoma is one of the most common type of malignant tumor in the urinary system. Previous studies have shown that epigenetic regulation mediated by the SWI/SNF chromatin remodeling complex plays an important role in the development of renal cell carcinoma. DPF3 is one of functional components of the SWI/SNF complex and expressed two splice isoforms, namely DPF3a and DPF3b. In our previous work, we found that DPF3 is up-regulated in patients with renal cell carcinoma, and overexpression of DPF3a significantly promotes the proliferation of renal cancer cells. Moreover, phosphorylated DPF3a by the protein kinase CK2 could specifically binds to cytoskeleton-associated proteins, whose expression level is significantly correlated with the survival rate of patients with renal cell carcinoma. In this proposal, we will use cellular and animal models to explore the role of DPF3 in renal cell carcinoma. Here, we aim to determine the upstream regulatory pathway of DPF3 and understand how DPF3 regulates its target genes through epigenetic mechanisms. The proposed project will further reveal the regulatory role of DPF3 in the development and progression of renal cell carcinoma, and provide novel directions for the development of biomarkers and therapeutic targets for renal cell carcinoma.

肾细胞癌是泌尿系统中最为常见的恶性肿瘤。研究表明，SWI/SNF染色体重塑复合体介导的表观遗传调控机制在肾细胞癌的发展中发挥重要作用。DPF3是SWI/SNF复合体的一个功能亚基，含有DPF3a和DPF3b两个剪接异构体。我们的前期研究发现，DPF3在肾细胞癌患者中表达上调，过表达DPF3a显著促进肾癌细胞的增殖；DPF3a被蛋白激酶CK2磷酸化后与细胞骨架相关蛋白特异性结合，这些蛋白的表达水平与肾细胞癌患者的生存率显著相关。在此基础上，本项目将利用细胞和动物模型深入研究DPF3在肾细胞癌中的作用，探索DPF3的上游调控通路，以及DPF3如何通过表观遗传机制调控下游靶基因。本课题将进一步揭示DPF3在肾细胞癌发生发展中的分子调控机制，为寻找肾细胞癌新型生物标记物和治疗靶点提供方向。

DPF3是SWI/SNF染色体重塑复合物的一个功能亚基，一项全基因组关联研究发现DPF3和透明细胞肾细胞癌(ccRCC)的发生发展显著相关，然而其具体的功能和作用机制尚不清楚。在本项目中，我们通过细胞和动物实验证实DPF3a(DPF3的短异构体)可以在体外和体内促进肾癌细胞迁移，这与DPF3a在ccRCC患者的转移灶中显着上调相一致。我们发现DPF3a与TGF-β信号通路的核内抑制因子SNIP1特异性相互作用，并通过SNIP1与TGF-β信号通路的主要转录调节因子SMAD4和p300组蛋白乙酰转移酶(HAT)形成复合物，从而共同调节下游基因的表达。从机制上讲，DPF3a的结合释放了SNIP1对p300HAT活性的抑制作用，导致局部组蛋白乙酰化水平增加，从而促进细胞迁移相关基因的转录激活。总之，我们的研究结果揭示了DPF3促进ccRCC转移的新功能，并进一步建立了SWI/SNF亚基与ccRCC之间的联系。