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

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 () and Canhua Huang ()
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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
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

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36708-5

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