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FBXO7 Ubiquitinates PRMT1 to Suppress Serine Synthesis and Tumor Growth in HCC

ABSTRACT: Cancer cells are often addicted to de novo serine synthesis to support their survival and rapid proliferation. However, how serine synthesis is regulated in cancer is not well understood. Our recent report demonstrated that protein arginine methyltransferase 1 (PRMT1) is upregulated in hepatocellular carcinoma (HCC) and methylates phosphoglycerate dehydrogenase (PHGDH, the first and rate-limiting enzyme in serine synthesis) at arginine 236, thereby activating PHGDH and promoting serine synthesis. Nevertheless, the mechanisms underlying upregulation of PRMT1 and regulation of PRMT1-PHGDH axis in HCC remain unknown. Here, using label-free quantitative proteomics analysis, we identified the potential interacting proteins of PRMT1.

ORGANISM(S): Homo Sapiens

SUBMITTER: Kui Wang

PROVIDER: PXD049069 | iProX | Thu Feb 01 00:00:00 GMT 2024

REPOSITORIES: iProX

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Project description:D-3-Phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95) is a necessary enzyme for de novo L-serine biosynthesis via the phosphorylated pathway. We demonstrated previously that Phgdh is expressed exclusively by neuroepithelium and radial glia in developing mouse brain and later mainly by astrocytes. Mutations in the human PHGDH gene cause serine deficiency disorders (SDD) associated with severe neurological symptoms such as congenital microcephaly, psychomotor retardation, and intractable seizures. We recently demonstrated that genetically engineered mice, in which the gene for Phgdh has been disrupted, have significantly decreased levels of serine and glycine, and exhibit malformation of brain such as microcephaly. The Phgdh null (KO) embryos exhibit lethal phenotype after gestational day 14, indicating that the phosphorylated pathway is essential for embryogenesis, especially for brain development. It is worth noting that the Phgdh knockout (KO) embryos primarily displayed microcephaly, which is the most conspicuous phenotype of patients with SDD. Thus, Phgdh KO mice are a useful animal model for studying the effect of diminished L-serine levels on development of the central nervous system and other organs. To better understand the mechanism underlying the molecular pathogenesis of SDD, we sought to examine whether gene expression is altered in the Phgdh KO mouse model. We identify genes that have altered expression in the head of the Phgdh KO embryos using the GeneChip array. Some of the genes identified by this method belong in functional categories that are relevant to the biochemical and morphological aberrations of the Phgdh deletion. Experiment Overall Design: Total RNA samples were prepared from head tissues from 2 embryos of Phgdh knockout and littermate wild-type controls. Experiment Overall Design: RNA of 4 biological replicates was hybridized to Affymetrix Mouse Genome 430 2.0 arrays. Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.

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FBXO7 Ubiquitinates PRMT1 to Suppress Serine Synthesis and Tumor Growth in HCC

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