2. Academic Validation
  3. PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma

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

  • Nat Commun. 2023 Feb 23;14(1):1011. doi: 10.1038/s41467-023-36708-5.
Kui Wang # 1,  Li Luo # 2 3,  Shuyue Fu # 1,  Mao Wang 1,  Zihao Wang 4,  Lixia Dong 1,  Xingyun Wu 1,  Lunzhi Dai 1,  Yong Peng 1,  Guobo Shen 1,  Hai-Ning Chen 4,  Edouard Collins Nice 5,  Xiawei Wei 6,  Canhua Huang 7
Affiliations

Affiliations

  • 1 West China School of Basic Medical Sciences & Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.
  • 2 Center for Reproductive Medicine, Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, PR China.
  • 3 Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, PR China.
  • 4 Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.
  • 5 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia.
  • 6 Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, PR China. xiaweiwei@scu.edu.cn.
  • 7 West China School of Basic Medical Sciences & Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China. hcanhua@hotmail.com.
  • # Contributed equally.
PMID: 36823188 DOI: 10.1038/s41467-023-36708-5
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.

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