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

Author

Listed:
  • Li Luo

    (Sichuan University
    Sichuan University
    Ministry of Education)

  • 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)

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.

Suggested Citation

  • Li Luo & Xingyun Wu & Jiawu Fan & Lixia Dong & Mao Wang & Yan Zeng & Sijia Li & Wenyong Yang & Jingwen Jiang & Kui Wang, 2024. "FBXO7 ubiquitinates PRMT1 to suppress serine synthesis and tumor growth in hepatocellular carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49087-2
    DOI: 10.1038/s41467-024-49087-2
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    1. Kui Wang & Li Luo & Shuyue Fu & Mao Wang & Zihao Wang & Lixia Dong & Xingyun Wu & Lunzhi Dai & Yong Peng & Guobo Shen & Hai-Ning Chen & Edouard Collins Nice & Xiawei Wei & Canhua Huang, 2023. "PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Mylène Tajan & Marc Hennequart & Eric C. Cheung & Fabio Zani & Andreas K. Hock & Nathalie Legrave & Oliver D. K. Maddocks & Rachel A. Ridgway & Dimitris Athineos & Alejandro Suárez-Bonnet & Robert L. , 2021. "Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
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