2. Academic Validation
  3. FBXO7 ubiquitinates PRMT1 to suppress serine synthesis and tumor growth in hepatocellular carcinoma

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

  • Nat Commun. 2024 Jun 5;15(1):4790. doi: 10.1038/s41467-024-49087-2.
Li Luo # 1 2 3,  Xingyun Wu # 1,  Jiawu Fan # 1,  Lixia Dong 1,  Mao Wang 1,  Yan Zeng 1,  Sijia Li 1,  Wenyong Yang 4,  Jingwen Jiang 5,  Kui Wang 6
Affiliations

Affiliations

  • 1 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.
  • 2 Center for Reproductive Medicine, Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, 610041, Chengdu, P. R. China.
  • 3 Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, 610041, Chengdu, P. R. China.
  • 4 Department of Neurosurgery, Medical Research Center, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, 610014, Chengdu, P.R. China.
  • 5 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. jjwcn@foxmail.com.
  • 6 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. kuiwang@scu.edu.cn.
  • # Contributed equally.
PMID: 38839752 DOI: 10.1038/s41467-024-49087-2
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.

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