Membrane-Bound O-Acyltransferase 7 (MBOAT7) is a Key Regulator of Glycolysis in Clear Cell Renal Carcinoma
AbstractObjectiveThe most common and deadliest urological cancer is clear cell Renal Cell Carcinoma (ccRCC). ccRCC is characterized by striking reorganization of both carbohydrate and lipid metabolism. It was recently demonstrated that lipid remodeling enzyme Membrane-Bound O-Acyltransferase 7 (MBOAT7) that generates phosphatidylinositol (PI) is important for the ccRCC progression. However, whether MBOAT7-driven PI remodeling is associated with other metabolic alterations commonly found in ccRCC is poorly understood.MethodsMBOAT7 deficient ccRCC cell lines were generated by genome editing, and were characterized by a general reduction in glycolytic capactiy. Using targeted metabolomics approach in Caki-1 cells, we measured the glycolytic intermediates and the relative expression of key glycolytic enzymes. We also measured basal respiration and maximal respiration with MBOAT7 deficiency in the presence of glucose. Lastly, in vivo xenograft studies were performed with parental and MBOAT7 deficient cells.ResultsMBOAT7 deficiency was associated with a reduction in glycolytic gene expression and protein abundance. In parallel, we found that glycolytic intermediates similarly decreased which may contribute to a reduction in glycolysis. MBOAT7 deficiency reduces basal respiration and maximal respiration. Similarly, we see maximum glycolytic capacity also reduced with MBOAT7 loss of function. Finally, the in vivo xenograft demonstrated MBOAT7 knockout significantly increased overall survival and reduced glycolytic HK2 protein abundance in vivo.ConclusionsOur work highlights MBOAT7 as a key regulator of glycolysis in ccRCC. Our data provides additional evidence that suggests MBOAT7 as a novel target to regulate tumor growth in vivo.
