Department of Biochemistry and Molecular Biology, Hunan Province Key Laboratory of Basic and Applied Hematology, Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Xiangya School of Medicine, Central South University, Changsha, China.
Yiyang Key Laboratory of Chemical Small Molecule Anti-Tumor Targeted Therapy, Department of Scientific Research, Yiyang Medical College, Yiyang, 413000, China.
Cell Death Dis. 2024 May 6;15(5):319. 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.
精氨酸琥珀酸合成酶（ASS1）是尿素循环中的关键酶，在许多癌症中作为肿瘤抑制因子发挥作用。迄今为止，ASS1 的抗癌机制尚未完全阐明。在这里，我们发现磷酸甘油酸脱氢酶（PHGDH），即丝氨酸合成的关键限速酶，是与 ASS1 相互作用的关键蛋白。我们的研究结果表明，ASS1 可直接与 PHGDH 结合，并促进其泛素化介导的降解，从而抑制丝氨酸合成，进而抑制肿瘤发生。重要的是，PHGDH 敲除可强烈削弱 ASS1 的肿瘤抑制作用。此外，当丝氨酸和甘氨酸耗尽时，ASS1 敲除和敲低部分挽救了细胞增殖，而添加丝氨酸和甘氨酸可恢复 ASS1 过表达对细胞增殖的抑制作用。这些发现揭示了 ASS1 的新作用，并表明 ASS1/PHGDH 丝氨酸合成途径是癌症治疗的有前途的靶点。
