Oxidative Stress from DGAT1 Oncoprotein Inhibition in Melanoma Suppresses Tumor Growth when ROS Defenses are also Breached

Dysregulated cellular metabolism is a cancer hallmark for which few druggable oncoprotein targets have been identified. Increased fatty acid (FA) acquisition allows cancer cells to meet their heightened membrane biogenesis, bioenergy, and signaling needs. Excess FA are toxic to non-transformed cells, but surprisingly not to cancer cells. Molecules underlying this cancer adaptation may provide alternative drug targets. Here, we demonstrate that Diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral to triacylglyceride synthesis and lipid droplet formation, is frequently up-regulated in melanoma, allowing melanoma cells to tolerate excess FA. DGAT1 over-expression alone transformed p53-mutant zebrafish melanocytes and cooperated with oncogenic BRAF or NRAS for more rapid melanoma formation. Antagonism of DGAT1 induced oxidative stress in melanoma cells, which adapt by upregulating cellular reactive oxygen species (ROS) defenses. We show that inhibiting both DGAT1 and superoxide dismutase (SOD) 1 profoundly suppressed tumor growth through eliciting intolerable oxidative stress.