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

Wensong Luo, Zizheng Zou, Yuan Nie, Junli Luo, Zhengnan Ming, Xiyuan Hu, Tiao Luo, Min Ouyang, Mingquan Liu, Huicheng Tang, Yuanzhu Xie, Kunjian Peng, Ling Chen, Jiang Zhou, Zhiyong Luo

Cell death & disease 2024 May 06

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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. © 2024. The Author(s).

Citation

Wensong Luo, Zizheng Zou, Yuan Nie, Junli Luo, Zhengnan Ming, Xiyuan Hu, Tiao Luo, Min Ouyang, Mingquan Liu, Huicheng Tang, Yuanzhu Xie, Kunjian Peng, Ling Chen, Jiang Zhou, Zhiyong Luo. ASS1 inhibits triple-negative breast cancer by regulating PHGDH stability and de novo serine synthesis. Cell death & disease. 2024 May 06;15(5):319