The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ

Abstract

Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Mounting evidence indicates key roles of glutamine transporters and glutaminase activity in cancer glutamine metabolism. Here, we show that the EphA2 receptor tyrosine kinase activates YAP and TAZ (YAP/TAZ), transcriptional co-activators of the TEAD family of transcription factors, to promote glutamine metabolism in models of HER2-positive breast cancer. EphA2 overexpression induced nuclear accumulation of YAP and TAZ and increased expression of YAP/TAZ target genes. Inhibition of Rho or ROCK kinase abolished EphA2-dependent YAP/TAZ nuclear localization, suggesting Rho signaling as a critical intermediary. Silencing of YAP or TAZ significantly reduced intracellular glutamate, through differential regulation of SLC1A5 and GLS, respectively. Indeed, the regulatory DNA elements of both SLC1A5 and GLS contain TEAD binding sites and were bound by TEAD4 in an EphA2-dependent manner. In human breast cancer, EphA2 expression positively correlates with YAP and TAZ, as well as GLS and SLC1A5. While high expression of EphA2 predicts enhanced metastatic potential and poor survival, increased EphA2 expression rendered HER2-positive breast cancer cells more sensitive to glutaminase inhibition. Together, these findings define a novel mechanism of EphA2-mediated YAP/TAZ activation to promote glutaminolysis through upregulation of GLS and SLC1A5 in HER2+ breast cancer.

The Human SLC1A5 (ASCT2) Amino Acid Transporter: From Function to Structure and Role in Cell Biology

“…In breast cancer HR-positive, c-Myc regulates different proteins involved in glutamine metabolism including ASCT2 and glutaminase (Gao et al, 2009 ; Chen et al, 2015 ). In the same cells, as well as in a mouse model, a molecular mechanism of activation of ASCT2 expression via the tyrosine kinase receptor EphA2 has been recently reported (Edwards et al, 2017 ). The importance of ASCT2 in breast cancers is demonstrated also by the activation of ubiquitin ligase RNF5, ascribed to chemotherapy-induced ER stress, that leads to degradation of glutamine transporters including ASCT2 (Jeon et al, 2015 ; Moses and Neckers, 2015 ).…”

Microenvironmental Metabolism Regulates Antitumor Immunity

“…Identification of metabolic targets that are selectively utilized in tumor cells may greatly improve antitumor immunity by avoiding detrimental effects on the immune cells. For example, the receptor tyrosine kinase EphA2 promotes glutamine metabolism in HER2-positive and triple-negative breast cancer cells (67,68), but it is not expressed in the T cells (69). Targeting EphA2 may selectively inhibit glutaminolysis in tumor cells while simultaneously avoiding similar effects on T cells.…”

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.…”

“…Uptake of amino acids is also affected by YAP and TAZ. For instance, YAP and TAZ stimulate transcription of SLC1A5, SLC7A5, and SLC38A1 (Edwards et al, 2017;Hansen et al, 2015;Park et al, 2016), which are the highaffinity amino acid transporters particularly important for amino acid uptake when their concentrations are low. Therefore, in addition to enhanced cellular amino acid metabolism by induction of metabolic enzymes, active YAP and TAZ confer cells with the ability to uptake amino acids to meet high substrate demands in growing cells.…”