West China School of Basic Medical Sciences & Forensic Medicine, State Key Laboratory of Biotherapy, West China Hospital, West China School of Public Health and West China Fourth Hospital, Sichuan University, 610041, Chengdu, P. R. China.
Center for Reproductive Medicine, Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, 610041, Chengdu, P. R. China.
Nat Commun. 2024 Jun 5;15(1):4790. doi: 10.1038/s41467-024-49087-2.
Cancer cells are often addicted to serine synthesis to support growth. How serine synthesis is regulated in cancer is not well understood. We recently demonstrated protein arginine methyltransferase 1 (PRMT1) is upregulated in hepatocellular carcinoma (HCC) to methylate and activate phosphoglycerate dehydrogenase (PHGDH), thereby promoting serine synthesis. However, the mechanisms underlying PRMT1 upregulation and regulation of PRMT1-PHGDH axis remain unclear. Here, we show the E3 ubiquitin ligase F-box-only protein 7 (FBXO7) inhibits serine synthesis in HCC by binding PRMT1, inducing lysine 37 ubiquitination, and promoting proteosomal degradation of PRMT1. FBXO7-mediated PRMT1 downregulation cripples PHGDH arginine methylation and activation, resulting in impaired serine synthesis, accumulation of reactive oxygen species (ROS), and inhibition of HCC cell growth. Notably, FBXO7 is significantly downregulated in human HCC tissues, and inversely associated with PRMT1 protein and PHGDH methylation level. Overall, our study provides mechanistic insights into the regulation of cancer serine synthesis by FBXO7-PRMT1-PHGDH axis, and will facilitate the development of serine-targeting strategies for cancer therapy.
癌细胞通常依赖丝氨酸合成来支持生长。然而，癌症中丝氨酸合成的调控机制尚不清楚。我们最近的研究表明，蛋白质精氨酸甲基转移酶 1（PRMT1）在肝细胞癌（HCC）中上调，以甲基化并激活磷酸甘油酸脱氢酶（PHGDH），从而促进丝氨酸合成。然而，PRMT1 上调的机制以及 PRMT1-PHGDH 轴的调控仍不清楚。在这里，我们发现 E3 泛素连接酶 F-box 蛋白 7（FBXO7）通过与 PRMT1 结合，诱导赖氨酸 37 泛素化，并促进 PRMT1 的蛋白酶体降解，从而抑制 HCC 中的丝氨酸合成。FBXO7 介导的 PRMT1 下调使 PHGDH 的精氨酸甲基化和激活受损，导致丝氨酸合成减少、活性氧（ROS）积累和 HCC 细胞生长抑制。值得注意的是，FBXO7 在人类 HCC 组织中显著下调，与 PRMT1 蛋白和 PHGDH 甲基化水平呈负相关。总之，我们的研究为 FBXO7-PRMT1-PHGDH 轴调节癌症丝氨酸合成提供了机制上的见解，并将促进针对癌症治疗的丝氨酸靶向策略的发展。
