The Epithelial to Mesenchymal Transition Promotes Glutamine Independence by Suppressing GLS2 Expression

Abstract

Identifying bioenergetics that facilitate the epithelial to mesenchymal transition (EMT) in breast cancer cells may uncover targets to treat incurable metastatic disease. Metastasis is the number one cause of cancer-related deaths; therefore, it is urgent to identify new treatment strategies to prevent the initiation of metastasis. To characterize the bioenergetics of EMT, we compared metabolic activities and gene expression in cells induced to differentiate into the mesenchymal state with their epithelial counterparts. We found that levels of <i>GLS2</i>, which encodes a glutaminase, are inversely associated with EMT. <i>GLS2</i> down-regulation was correlated with reduced mitochondrial activity and glutamine independence even in low-glucose conditions. Restoration of <i>GLS2</i> expression in <i>GLS2</i>-negative breast cancer cells rescued mitochondrial activity, enhanced glutamine utilization, and inhibited stem-cell properties. Additionally, inhibition of expression of the transcription factor FOXC2, a critical regulator of EMT in <i>GLS2</i>-negative cells, restored GLS2 expression and glutamine utilization. Furthermore, in breast cancer patients, high <i>GLS2</i> expression is associated with improved survival. These findings suggest that epithelial cancer cells rely on glutamine and that cells induced to undergo EMT become glutamine independent. Moreover, the inhibition of EMT leads to a GLS2-directed metabolic shift in mesenchymal cancer cells, which may make these cells susceptible to chemotherapies.