YAP modulates mitochondrial function and sensitive to NAMPT inhibition in triple negative breast cancer cells

YAP and TAZ coordinate several NAD+-dependent processes like glycolysis, fatty acid oxidation and glutaminolysis in nutrient-deprivation conditions. However, correlations between NAD(H) levels and YAP/TAZ metabolic function are still poorly understood. We showed that stable silencing of YAP in the triple-negative breast cancer (TNBC) cell line MDAMB231 (MDA shYAP) rescued the toxicity of the NAD+ depletion agent FK866, both in 2D and in 3D culturing, prevented ROS accumulation and apoptosis. As MDA shYAP cells phenocopy the behavior of FK866-resistant MDAMB231 cells (RES), a comparative proteomic study between these cells lines was performed. We identified a deregulation of cell cycle in both MDA shYAP and RES, which prevents apoptosis initiation upon FK866 treatment. Moreover, we found an upregulation of mitochondrial proteins, in line with an increased mitochondrial biogenesis, function and mass, as previously observed for RES. Overall, we showed a YAP-dependent rewiring of mitochondrial metabolism and cell cycle checkpoints, which sustains the acquirement of resistance to FK866 in TNBC.