Glycine Decarboxylase Regulates Renal Carcinoma Progression via Interferon Stimulated Gene Factor 3-Mediated Pathway

Renal cell carcinoma (RCC) is considered as a "metabolic disease" due to various perturbations in metabolic pathways that could drive cancer development. Glycine decarboxylase (GLDC) is a mitochondrial enzyme that takes part in the oxidation of glycine to support nucleotide biosynthesis via transfer of one-carbon units. Herein, we aimed to investigate the potential role of GLDC in RCC development. We found that GLDC depletion diminished nucleotide synthesis and promoted reactive oxygen species (ROS) generation to repress RCC progression, which was reversed by repletion of deoxynucleosides. Additionally, in vitro and in vivo studies revealed that GLDC plays an important role in regulation of proliferation and tumor growth via interferon stimulated gene factor 3 (ISGF3)-mediated pathway. Expressions of interferon regulatory factor 9 (IRF9) and signal transducer and activator of transcription 2 (STAT2) were elevated in GLDC knock-downed cells and decreased in GLDC over-expressed cells. Double knock-down of STAT2 and IRF9 in GLDC-deficient cells rescued GLDC depletion-induced decrease in cell proliferation. Furthermore, GLDC depletion increased cisplatin-and doxorubicin-induced DNA damage through ISGF3 pathway, leading to cell cycle dysregulation and increased mitotic catastrophe. These findings reveal that GLDC regulates RCC progression via ISFG3-mediated pathway and offers a promising strategy for RCC treatment.