PDF(Pubmed)
Abstract：
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.
摘要：
精氨酸琥珀酸合酶（ASS1），尿素循环中的关键酶，在许多癌症中充当肿瘤抑制因子。迄今为止,ASS1的抗癌机制尚未完全阐明。这里,我们发现磷酸甘油酸脱氢酶（PHGDH），丝氨酸合成中的关键限速酶，是与ASS1相互作用的关键蛋白。我们的结果表明ASS1直接与PHGDH结合并促进其泛素化介导的降解以抑制丝氨酸合成，从而抑制肿瘤发生。重要的是,ASS1的肿瘤抑制作用被PHGDH基因敲除强烈取消.此外,当丝氨酸和甘氨酸耗尽时，ASS1敲除和敲除部分挽救了细胞增殖，通过添加丝氨酸和甘氨酸恢复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希望的靶标。
