Abstract 6954: Glycine decarboxylase regulates renal carcinoma progression and DNA damage response via interferon stimulated gene factor 3-mediated pathway

Abstract

Abstract Glycine decarboxylase (GLDC) is a mitochondrial enzyme of glycine cleavage system which catalyzes glycine to donate for one-carbon metabolism. It is implicated as a tumor suppressor in hepatocellular carcinoma but as an oncogene in lung cancer. Although GLDC expression in the kidney is second highest next to the liver, the role of GLDC in the kidney remains unclear. Thus, this study was designed to determine the role of GLDC in renal carcinoma. We found markedly increased expressions of GLDC in patients with renal cell carcinoma (RCC) classified as poor-risk group based on the Memorial Sloan Kettering Cancer Center prognostic model. In vitro studies revealed that cellular proliferation, colony formation was decreased in GLDC-deficient renal carcinoma cells. Additionally in vivo xenograft studies with GLDC-deficient and -overexpressing cells also revealed that tumor sizes were noticeably decreased in GLDC-deficient cell-injected mice while those were increased in GLDC-overexpressing cell-injected mice. Mechanistically, we found GLDC regulates renal carcinoma progression via interferon (IFN) stimulated gene factor 3 (ISGF3)-mediated pathway. Expressions of IRF9 and STAT2 were increased in GLDC-deficient cells while those were decreased in GLDC-overexpressing cells. Upon inducing expression of ISGF3 subunits, GLDC deletion elevated DNA damage, mitotic catastrophe, mitochondrial deficiency induced by chemotherapy. Finally, GLDC knockdown diminished pyrimidine synthesis to impair renal cancer progression. In summary, our finding reveals that GLDC regulates renal carcinoma progression and DNA damage response via ISFG3-medated pathway and lays a scientific foundation that could support a therapeutic strategy that targets GLDC for the treatment of renal carcinoma. Citation Format: Jin Young Kim, Byung Hoon Kim, Misun Choe, Thi Tuyet Mai Pham, Mikyung Kim, Ji Hae Seo, So Jin Shin. Glycine decarboxylase regulates renal carcinoma progression and DNA damage response via interferon stimulated gene factor 3-mediated pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6954.