ASS1 inhibits triple-negative breast cancer by regulating PHGDH stability and de novo serine synthesis

• Published in: Cell death & disease Vol. 15; no. 5; p. 319
• Main Authors: Luo, Wensong, Zou, Zizheng, Nie, Yuan, Luo, Junli, Ming, Zhengnan, Hu, Xiyuan, Luo, Tiao, Ouyang, Min, Liu, Mingquan, Tang, Huicheng, Xie, Yuanzhu, Peng, Kunjian, Chen, Ling, Zhou, Jiang, Luo, Zhiyong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.05.2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 13/109; 14; 14/19; 631/67; 631/67/1347; 64; 64/60; 82; 82/58; 96; 96/95; Amino acids; Animals; Antibodies; Argininosuccinate synthase; Argininosuccinate Synthase - genetics; Argininosuccinate Synthase - metabolism; Biochemistry; Biomedical and Life Sciences; Biosynthesis; Breast cancer; Cancer therapies; Cell Biology; Cell Culture; Cell growth; Cell Line, Tumor; Cell Proliferation; Disease; Enzymes; Experiments; Female; Gene amplification; Glycine - metabolism; Humans; Immunology; Laboratory animals; Life Sciences; Liver cancer; Medical prognosis; Medical research; Melanoma; Metabolism; Metabolites; Mice; Mice, Nude; Pancreatic cancer; Penicillin; Phosphoglycerate dehydrogenase; Phosphoglycerate Dehydrogenase - genetics; Phosphoglycerate Dehydrogenase - metabolism; Prostate cancer; Protein biosynthesis; Proteins; Serine; Serine - biosynthesis; Serine - metabolism; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumor suppressor genes; Tumorigenesis; Tumors; Ubiquitination
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06672-z

Argininosuccinate synthase (ASS1), a critical enzyme in the urea cycle, acts as a tumor suppressor in many cancers. To date, the anticancer mechanism of ASS1 has not been fully elucidated. Here, we found that phosphoglycerate dehydrogenase (PHGDH), a key rate-limiting enzyme in serine synthesis, is a pivotal protein that interacts with ASS1. Our results showed that ASS1 directly binds to PHGDH and promotes its ubiquitination-mediated degradation to inhibit serine synthesis, consequently suppressing tumorigenesis. Importantly, the tumor suppressive effects of ASS1 were strongly abrogated by PHGDH knockout. In addition, ASS1 knockout and knockdown partially rescued cell proliferation when serine and glycine were depleted, while the inhibitory effect of ASS1 overexpression on cell proliferation was restored by the addition of serine and glycine. These findings unveil a novel role of ASS1 and suggest that the ASS1/PHGDH serine synthesis pathway is a promising target for cancer therapy.