Abstract 1194: O-GlcNAcylation regulates breast cancer lipid metabolism via sterol regulatory element binding protein 1

Abstract

Abstract The Warburg hypothesis states that cancer cells display altered metabolic features to support their rapid growth and biosynthetic demands including increased glycolytic flux to synthesize necessary building blocks required by growing cells. Increased glucose uptake feeds not only glycolysis but other glucose dependent pathways as well, such as the Hexosamine Biosynthetic Pathway (HBP). HBP diverts fructose-6-phosphate from glycolysis to produce UDP-GlcNAc, the amino sugar donor to O-GlcNAc Transferase (OGT). Analagous to phosphorylation, O-GlcNAcylation can alter protein function and stability and itself is altered in several disease states. Our lab has demonstrated that OGT and O-GlcNAcylation are elevated in breast cancer and that expression of this enzyme is critical for various cancer phenotypes such as avoidance of ER stress and apoptosis, supporting invasion and metastasis and more recently promotion of Warburg effect. Here we demonstrate that OGT and O-GlcNAc are important for lipid metabolism in cancer cells through regulation of transcription factor SREBP-1 and its targets. Metabolic profiling revealed that OGT depletion in MDA-MB-231 cells decreased various lipids metabolites measured, including long-chain fatty acids, lysolipids and essential fatty acids. OGT suppression results in a decrease in SREBP-1 protein and mRNA and reduction of its transcriptional targets, enzymes involved in lipid synthesis, in both breast cancer cells and highly lipogenic normal tissue, the mammary fat pad. Over-expression of SREBP-1 blocks apoptosis induced by OGT suppression in 2D and 3D culture. Overall, we show that OGT and O-GlcNAc play a role in yet another process critical to cancer cell survival, lipid metabolism. Citation Format: Valerie L. Sodi, Zachary Bacigalupa, Christina Ferrer, Mauricio Reginato. O-GlcNAcylation regulates breast cancer lipid metabolism via sterol regulatory element binding protein 1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1194. doi:10.1158/1538-7445.AM2015-1194