Figure 6. Schematic diagram of the SAHA induced blockage of glioma glutamate release.

Summary of experimental data reveal that malignant brain tumors secrete neurotoxic concentrations of glutamate via xCT transporter, which is regulated by sestrin2 and ATF4. While sestrin2 controls Keap1 and Nrf2, ATF4 regulates xCT-expression directly on the promotor site. Treatment with SAHA affects ATF4 leading to a reduced xCT-expression with subsequent reduced glutamate release into the extracellular space. SAHA alleviates xCT-dependent cell death probably by this transcriptional pathway.