One-carbon(1C) metabolism is highlydysregulated in cancer. While serine serves as the main donor offolate-mediated 1C units, recent studies reveal the importance of metaboliccontribution by other 1C donors in tumors.
Studyingthe contribution of glycine to 1C metabolism, we found major increase in theexpression of glycine cleavage system (GCS) genes specifically inhepatocellular carcinoma (HCC). We developed a Systems Biology method fordirectly quantifying GCS flux by integrating 13C and 14Ctracers, and computational modeling – a highly challenging task considering thevariety of pathways oxidizing glycine and serine, and the rapid interconversionof these two amino acids. We show, for the first time, that glycine-derived 1Cunits support purine and pyrimidine biosynthesis in tumors (via shuttling ofglycine-derived formate to cytosol) and that this occursspecifically in HCC.
Geneticsilencing of glycine decarboxylase (P-subunit of GCS) leads to mitochondrialdysfunction and halts HCC tumor growth in mouse models. Our work establishesGCS as a novel target for HCC – the most common and highly malignant type ofprimary liver cancer, currently without an effective treatment.