YY2/PHGDH axis suppresses tumorigenesis by inhibiting tumor cell de novo serine biosynthesis

• Published in: Biomedicine & pharmacotherapy Vol. 165; p. 115006
• Main Authors: Li, Juan, Luo, Xinxin, Wei, Mankun, Li, Zhuolin, Li, Yanjun, Zhao, Hezhao, Miyagishi, Makoto, Kasim, Vivi, Wu, Shourong
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.09.2023; Elsevier
• Subjects: Amino acids metabolism; Metabolic reprogramming; PHGDH; Serine biosynthesis; Tumorigenesis; YY2; Amino acids metabolism; PHGDH; Tumorigenesis; YY2; Metabolic reprogramming; Serine biosynthesis
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.115006

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. [Display omitted] •YY2 downregulates tumor cell serine metabolism.•YY2 suppresses tumor cell de novo serine biosynthesis by suppressing PHGDH expression.•YY2 binds to PHGDH promoter and suppresses its transcriptional activity.•YY2-PHGDH axis suppresses tumor cell antioxidant defense and nucleotides synthesis.•YY2-PHGDH axis is crucial for suppressing tumorigenesis by inhibiting serine biosynthesis.