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

Abstract

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.

Interplay between YAP/TAZ and Metabolism

“…Being a source for nitrogen and carbon in an array of growth-promoting pathways, glutamine is particularly crucial for highly proliferative cells as seen in many malignant cells that display oncogene-dependent addictions to glutamine (Altman et al, 2016). Several studies indicate that many glutamine-metabolizing enzymes are transcriptionally governed by YAP (Bertero et al, 2016;Du et al, 2018;Edwards et al, 2017;Yang et al, 2018). Via TEAD, YAP binds to the TEAD-responsive elements in the promoter region of GLS1 to stimulate transcription, thereby promoting conversion of glutamine to glutamate.…”

“…Via TEAD, YAP binds to the TEAD-responsive elements in the promoter region of GLS1 to stimulate transcription, thereby promoting conversion of glutamine to glutamate. YAP also transcribes GOT1 and PSAT1, the enzyme responsible for breakdown of glutamine to a-ketoglutarate, to further supply fuel for mitochondrial ATP generation (Yang et al, 2018).…”

YAP nuclear‐cytoplasmic translocation is regulated by mechanical signaling, protein modification, and metabolism

“…In addition, LATS2, a tumor suppressor that is upstream of YAP, can also inhibit liver cholesterol accumulation by inhibiting SREBP (Aylon et al, 2016). TAZ/YAP activity is positively correlated with transaminase expression in patients with breast cancer, suggesting that transaminase is a potential target for treatment in patients with TAZ/YAP‐driven breast cancer (Yang et al, 2018) (Figure 4).…”

Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy

“…Increasing evidences suggest a central connection of mechanotransduction – including the YAP/TAZ pathway – with cellular metabolism (Santinon et al, 2018; Yang et al, 2018), and processes related to glucose consumption and Warburg metabolism (Bays et al, 2017; Enzo et al, 2015; Mo et al, 2015; Sorrentino et al, 2014; Wang et al, 2015). However, increased glycolysis alone is insufficient to meet the total metabolic demands of proliferating cells.…”