PRMT1介导的PHGDH精氨酸甲基化修饰在肝癌中的作用及分子机制研究

3-磷酸甘油酸脱氢酶（PHGDH）是丝氨酸生物合成途径的一个关键限速酶，在肿瘤发生发展中发挥重要作用，但其酶活调控机制尚不清楚。我们前期通过筛选PHGDH的相互作用蛋白，发现蛋白质精氨酸甲基转移酶PRMT1可与PHGDH发生相互作用。在PRMT1的作用下，PHGDH的精氨酸发生不对称二甲基化修饰。进一步研究初步表明，精氨酸甲基化修饰可增强PHGDH酶活，抑制PHGDH精氨酸甲基化修饰在细胞水平可阻抑肝癌细胞生长和转移。在此基础上，本项目拟明确PRMT1介导PHGDH发生精氨酸甲基化修饰的关键位点；利用细胞和动物模型，阐明PRMT1介导的PHGDH精氨酸甲基化修饰促进肝癌细胞生长和转移的分子机制；结合临床样本，明确PHGDH精氨酸甲基化修饰的病理学意义和潜在临床应用价值。通过本项目的实施，有望阐明精氨酸甲基化修饰通过调控PHGDH酶活促进肝癌发生发展的分子机制，为肝癌的临床治疗提供新思路。

3-phosphoglycerate dehydrogenase (PHGDH), a key rate-limiting enzyme in de novo serine biosynthesis pathway, plays an important role in tumorigenesis and tumor progression. However, the regulatory mechanism underlying the enzymatic activity of PHGDH still remains unclear. Through analyzing PHGDH-interacting proteins, we found that protein arginine methyltransferase 1 (PRMT1) can interact with PHGDH. PRMT1 is demonstrated to promote the arginine methylation of PHGDH in liver cancer cells. We further found that the arginine methylation elevates PHGDH activity. Inhibiting the arginine methylation of PHGDH markedly represses the growth and metastasis of liver cancer cells in vitro. In this project, we will identify the key methylated arginine residues of PHGDH. we will also investigate the mechanisms underlying PRMT1-mediated arginine methylation of PHGDH in promoting the growth and metastasis of liver cancer cells both in vitro and in vivo. Moreover, we will evaluate the pathological significance of PHGDH arginine methylation in liver cancer. Our study will provide new insights into the regulatory mechanism of PHGDH activity, which will facilitate the development of novel therapeutic strategies for liver cancer.