Phgdh, or PhosphoGlycerol Dehydrogenase, is a key enzyme in the serine biosynthesis pathway, catalyzing the conversion of 3-phosphoglycerate to 3-phosphohydroxypyruvate. Serine is crucial for DNA synthesis, antioxidant production, and is involved in one-carbon metabolism. Alterations in Phgdh expression and activity are associated with various biological processes and disease conditions, making genetic models valuable for studying its functions [1,2,3,4,5,6,7,8,9].

Knock-down of Phgdh in bladder cancer cells promoted ferroptosis and decreased cell proliferation, while also downregulating SLC7A11 expression. Mechanistically, Phgdh interacts with PCBP2, inhibiting its ubiquitination degradation, which in turn stabilizes SLC7A11 mRNA [1]. In breast cancer, loss of Phgdh in mice potentiated metastatic dissemination, as heterogeneous or low Phgdh expression in primary tumors was associated with decreased metastasis-free survival. Phgdh interacts with phosphofructokinase, and its loss activates the hexosamine-sialic acid pathway, leading to aberrant protein glycosylation and enhanced cell migration [2]. In macrophages, loss of Phgdh disrupted cellular metabolism and mitochondrial respiration essential for immunosuppressive M2 macrophage activation. Genetic ablation of Phgdh in macrophages from tumor-bearing mice attenuated tumor growth, reduced TAM infiltration, and shifted the M2-like TAM phenotype towards an M1-like phenotype [3]. In endothelial cells, genetic Phgdh ablation pruned over-sprouting vasculature, abrogated intratumoral hypoxia, and improved T-cell infiltration into glioblastoma tumors [4]. In hepatocellular carcinoma, blocking Phgdh methylation with a non-methylated peptide inhibited serine synthesis and restrained tumor growth in xenograft models [5]. In HCC, inactivation of Phgdh by RNAi knockdown or Nuclease technology knockout paralyzed the serine synthesis pathway, elevated ROS levels, and induced apoptosis upon Sorafenib treatment. The Phgdh inhibitor NCT-503 worked synergistically with Sorafenib to abolish HCC growth in vivo [9].

In conclusion, Phgdh plays essential roles in multiple biological processes such as cell proliferation, ferroptosis regulation, metastasis, macrophage activation, and tumor-associated vascular and metabolic regulation. Findings from Phgdh loss-of-function experiments, including those in KO/CKO mouse models, have significantly enhanced our understanding of its roles in bladder, breast, and liver cancers, as well as in macrophage-mediated immunosuppression and glioblastoma resistance to immunotherapy, providing potential therapeutic targets for these diseases.

References:

1. Shen, Liliang, Zhang, Junfeng, Zheng, Zongtai, Zhang, Wentao, Yao, Xudong. 2022. PHGDH Inhibits Ferroptosis and Promotes Malignant Progression by Upregulating SLC7A11 in Bladder Cancer. In International journal of biological sciences, 18, 5459-5474. doi:10.7150/ijbs.74546. https://pubmed.ncbi.nlm.nih.gov/36147463/

2. Rossi, Matteo, Altea-Manzano, Patricia, Demicco, Margherita, Rheenen, Jacco van, Fendt, Sarah-Maria. 2022. PHGDH heterogeneity potentiates cancer cell dissemination and metastasis. In Nature, 605, 747-753. doi:10.1038/s41586-022-04758-2. https://pubmed.ncbi.nlm.nih.gov/35585241/

3. Cai, Zhengnan, Li, Wan, Hager, Sonja, Heffeter, Petra, Weckwerth, Wolfram. 2024. Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through α-ketoglutarate and mTORC1 signaling. In Cellular & molecular immunology, 21, 448-465. doi:10.1038/s41423-024-01134-0. https://pubmed.ncbi.nlm.nih.gov/38409249/

4. Zhang, Duo, Li, Albert M, Hu, Guanghui, Gong, Yanqing, Fan, Yi. 2023. PHGDH-mediated endothelial metabolism drives glioblastoma resistance to chimeric antigen receptor T cell immunotherapy. In Cell metabolism, 35, 517-534.e8. doi:10.1016/j.cmet.2023.01.010. https://pubmed.ncbi.nlm.nih.gov/36804058/

5. Wang, Kui, Luo, Li, Fu, Shuyue, Wei, Xiawei, Huang, Canhua. 2023. PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma. In Nature communications, 14, 1011. doi:10.1038/s41467-023-36708-5. https://pubmed.ncbi.nlm.nih.gov/36823188/

6. Pacold, Michael E, Brimacombe, Kyle R, Chan, Sze Ham, Boxer, Matthew B, Sabatini, David M. 2016. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. In Nature chemical biology, 12, 452-8. doi:10.1038/nchembio.2070. https://pubmed.ncbi.nlm.nih.gov/27110680/

7. Ma, Chunmin, Zheng, Ke, Jiang, Kun, Zhao, Yuzheng, Jiang, Yuhui. 2021. The alternative activity of nuclear PHGDH contributes to tumour growth under nutrient stress. In Nature metabolism, 3, 1357-1371. doi:10.1038/s42255-021-00456-x. https://pubmed.ncbi.nlm.nih.gov/34663976/

8. Lee, Chae Min, Hwang, Yeseong, Kim, Minki, Kim, Hyeonhui, Fang, Sungsoon. 2024. PHGDH: a novel therapeutic target in cancer. In Experimental & molecular medicine, 56, 1513-1522. doi:10.1038/s12276-024-01268-1. https://pubmed.ncbi.nlm.nih.gov/38945960/

9. Wei, Lai, Lee, Derek, Law, Cheuk-Ting, Wong, Carmen Chak-Lui, Wong, Chun-Ming. 2019. Genome-wide Nuclease technology library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC. In Nature communications, 10, 4681. doi:10.1038/s41467-019-12606-7. https://pubmed.ncbi.nlm.nih.gov/31615983/