Transcription Factor YY2 inhibits tumor cell glutamine catabolism by regulating GLS1 RNA splicing isoform GAC.

Amino acids metabolic reprogramming is critical for tumorigenesis. Alterations in amino acid metabolism are frequently observed in tumors and are crucial for fulfilling the demand for macromolecular biosynthesis, redox balance, and energy production in tumor cells. Despite its importance, the mechanism regulating amino acid metabolic reprogramming in tumor cells has not been completely elucidated. Herein, using colorectal cancer and hepatocarcinoma cells, we reveal that YY2 significantly reduced the transcriptional activity of glutaminase 1 (GLS1), which hydrolyzes glutamine to glutamate, by decreasing the expression of glutaminase C (GAC), a splicing isoform of GLS1. This, in turn, promoted glutamine accumulation while decreasing that of glutamate, leading to a drop in DNA and de novo glutathione synthesis, followed by a reduction in tumor cell proliferation and antioxidant capacity. Subsequently, we showed that YY2/GLS1-mediated inhibition of glutamine catabolism significantly suppressed tumorigenic potential in vivo. Critically, mutant YY2, often found in clinical tumor samples, failed to exert this effect. Together, these results identify YY2/GAC as a negative regulator of glutamine catabolism in tumor cells and reveal a novel molecular mechanism underlying the tumor-suppressive effect of YY2. Moreover, these findings suggest that YY2 could serve as an antitumor therapeutic agent by targeting glutamine metabolism.