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PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma

Author

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  • Kui Wang

    (West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Li Luo

    (West China Second University Hospital, Sichuan University
    Ministry of Education)

  • Shuyue Fu

    (West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Mao Wang

    (West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Zihao Wang

    (State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Lixia Dong

    (West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Xingyun Wu

    (West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Lunzhi Dai

    (West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Yong Peng

    (West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Guobo Shen

    (West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Hai-Ning Chen

    (State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Edouard Collins Nice

    (Monash University)

  • Xiawei Wei

    (State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University)

  • Canhua Huang

    (West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy)

Abstract

Serine synthesis is crucial for tumor growth and survival, but its regulatory mechanism in cancer remains elusive. Here, using integrative metabolomics and transcriptomics analyses, we show a heterogeneity between metabolite and transcript profiles. Specifically, the level of serine in hepatocellular carcinoma (HCC) tissues is increased, whereas the expression of phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme in serine biosynthesis pathway, is markedly downregulated. Interestingly, the increased serine level is obtained by enhanced PHGDH catalytic activity due to protein arginine methyltransferase 1 (PRMT1)-mediated methylation of PHGDH at arginine 236. PRMT1-mediated PHGDH methylation and activation potentiates serine synthesis, ameliorates oxidative stress, and promotes HCC growth in vitro and in vivo. Furthermore, PRMT1-mediated PHGDH methylation correlates with PHGDH hyperactivation and serine accumulation in human HCC tissues, and is predictive of poor prognosis of HCC patients. Notably, blocking PHGDH methylation with a TAT-tagged nonmethylated peptide inhibits serine synthesis and restrains HCC growth in an HCC patient-derived xenograft (PDX) model and subcutaneous HCC cell-derived xenograft model. Overall, our findings reveal a regulatory mechanism of PHGDH activity and serine synthesis, and suggest PHGDH methylation as a potential therapeutic vulnerability in HCC.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36708-5
    DOI: 10.1038/s41467-023-36708-5
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    1. 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.

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