Fig. 8: A schematic model of which STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells.

Usually, STAG2 inhibits ERK signaling by increasing DUSP6, while this signaling is overactivated upon STAG2 inactivation in BRAF-mutant thyroid cancer cells. Activated ERK promotes AKT/GSK3β signaling-mediated protein degradation of c-Myc via feedback suppression of HER3 transcription and RAS signaling. As a result, c-Myc downstream glutamine transporter and glutaminases such as GLS, GLS2 and SLC1A5 are down-regulated, thereby leading to reprogramming of glutamine metabolism and making BRAF-mutant thyroid cancer cells more sensitive to glutamine deprivation and glutaminase inhibitor.