Metabolic reprogramming is one of the key features of
tumors facilitating their rapid proliferation and adaptation to harsh microenvironments. Yin Yang 2 (YY2) has recently been reported as a
tumor suppressor downregulated in various types of
tumors; however, the molecular mechanisms underlying its
tumor-suppressive activity remain poorly understood. Furthermore, the involvement of YY2 in
tumor cell metabolic reprogramming remains unclear. Herein, we aimed to elucidate the novel regulatory mechanism of YY2 in the suppression of
tumorigenesis. Using transcriptomic analysis, we uncovered an unprecedented link between YY2 and
tumor cell
serine metabolism. YY2 alteration could negatively regulate the expression level of
phosphoglycerate dehydrogenase (PHGDH), the first
enzyme in the
serine biosynthesis pathway, and consequently,
tumor cell de novo
serine biosynthesis. Mechanistically, we revealed that YY2 binds to the PHGDH promoter and suppresses its transcriptional activity. This, in turn, leads to decreased production of
serine,
nucleotides, and cellular
reductants NADH and
NADPH, which subsequently suppresses tumorigenic potential. These findings reveal a novel function of YY2 as a regulator of the
serine metabolic pathway in
tumor cells and provide new insights into its
tumor suppressor activity. Furthermore, our findings suggest the potential of YY2 as a target for metabolic-based antitumor therapeutic strategies.