FBXO7 ubiquitinates PRMT1 to suppress serine synthesis and tumor growth in hepatocellular carcinoma

Li Luo, Xingyun Wu, Jiawu Fan, Lixia Dong, Mao Wang, Yan Zeng, Sijia Li, Wenyong Yang, Jingwen Jiang () and Kui Wang ()
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Li Luo: Sichuan University
Xingyun Wu: Sichuan University
Jiawu Fan: Sichuan University
Lixia Dong: Sichuan University
Mao Wang: Sichuan University
Yan Zeng: Sichuan University
Sijia Li: Sichuan University
Wenyong Yang: The Second Chengdu Hospital Affiliated to Chongqing Medical University
Jingwen Jiang: Sichuan University
Kui Wang: Sichuan University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49087-2

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