PRMT5介导的ΔNp63α蛋白精氨酸甲基化及其促舌鳞癌细胞迁移作用

p53家族蛋白ΔNp63α在多种鳞癌发生发展中起着重要作用，其受多种翻译后修饰调控，但未见关于其受甲基化修饰调节的报道。前期我们通过IP/MS鉴定出精氨酸甲基转移酶PRMT5与ΔNp63α直接结合；PRMT5特异性介导ΔNp63α的R561甲基化修饰，并影响∆Np63α与HSP90α等蛋白结合；舌鳞癌中PRMT5表达升高并降低总体生存率；PRMT5抑制ΔNp63α的转录激活功能，并依赖于其甲基转移酶活性促进舌鳞癌细胞迁移；同时敲低∆Np63α能挽救敲低PRMT5导致的迁移减慢。对于PRMT5如何调节∆Np63α转录因子活性、促进细胞迁移，是否在体内影响舌鳞癌转移，尚有待研究。本项目拟在细胞和动物水平以及临床样品中研究PRMT5对∆Np63α的调节，探究该调节在舌鳞癌细胞迁移和转移中的作用和机理。本项目对于理解舌鳞癌发展的分子机理，以及探索可能的舌鳞癌治疗策略，具有重要的理论意义。

The p53 family member ΔNp63α plays an important role in the development of a variety of squamous cell carcinoma. ΔNp63α is regulated by various post-translational modifications, but there is no report on its methylation modification. In the previous study, we identified the direct binding of arginine methyltransferase PRMT5 and ΔNp63α by IP / MS; we further confirmed that PRMT5 specifically mediates the single methylation and symmetric double methylation of arginine at R561 site of ΔNp63α, and affects the binding of ΔNp63α with other proteins, such as HSP90α. PRMT5 is often up-regulated in tongue squamous cell carcinoma (TSCC) and decreases overall survival of TSCC patients. PRMT5 inhibits the transactivity of ΔNp63α, as well as promotes migration of TSCC cells depending on its methyltransferase activity; on the other hand, knocking down of ΔNp63α can partially rescue the migration slowdown caused by PRMT5 knockdown. It remains unclear on how PRMT5 regulates the activity of ΔNp63α transcription factor, how PRMT5 promotes migration of TSCC cells, and whether PRMT5 affects metastasis of TSCC in vivo. This project aims to study the regulation of PRMT5 on ΔNp63α at the cellular and animal levels as well as in clinical samples, and to explore the role and mechanism of this regulation in cell migration and metastasis of TSCC. This project is of great theoretical significance to elucidate the molecular mechanism of TSCC progression, and to explore the possible treatment strategies of TSCC.