Glutamine‐utilizing transaminases are a metabolic vulnerability of TAZ/YAP‐activated cancer cells

The transcriptional regulators TAZ and YAP (TAZ/YAP) have emerged as pro‐tumorigenic factors that drive many oncogenic traits, including induction of cell growth, resistance to cell death, and activation of processes that promote migration and invasion. Here, we report that TAZ/YAP reprogram cellular energetics to promote the dependence of breast cancer cell growth on exogenous glutamine. Rescue experiments with glutamine‐derived metabolites suggest an essential role for glutamate and α‐ketoglutarate (AKG) in TAZ/YAP‐driven cell growth in the absence of glutamine. Analysis of enzymes that mediate the conversion of glutamate to AKG shows that TAZ/YAP induce glutamic–oxaloacetic transaminase (GOT1) and phosphoserine aminotransferase (PSAT1) expression and that TAZ/YAP activity positively correlates with transaminase expression in breast cancer patients. Notably, we find that the transaminase inhibitor aminooxyacetate (AOA) represses cell growth in a TAZ/YAP‐dependent manner, identifying transamination as a potential vulnerable metabolic requirement for TAZ/YAP‐driven breast cancer. Synopsis Elevated levels of the transcriptional regulators TAZ/YAP, key effectors of Hippo pathway signalling, mediate breast cancer cell growth dependence on exogenous glutamine. Cancer cells with high TAZ/YAP activity are sensitive to transaminase inhibition. High TAZ/YAP levels alter cellular energetics to promote breast cancer cell growth dependence on exogenous glutamine. TAZ/YAP promote the expression of glutamic–oxaloacetic transaminase (GOT1) and phosphoserine aminotransferase (PSAT1). Transaminase inhibition represses breast cancer cell growth in a TAZ/YAP dependent manner. Graphical Abstract Elevated levels of the transcriptional regulators TAZ/YAP, key effectors of Hippo pathway signalling, mediate breast cancer cell growth dependence on exogenous glutamine. Cancer cells with high TAZ/YAP activity are sensitive to transaminase inhibition.