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

Wensong Luo1, Zizheng Zou1,2, Yuan Nie1

  • 1Department 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.

Cell Death & Disease
|May 6, 2024
PubMed

Insights

Argininosuccinate synthase (ASS1) suppresses tumors by degrading phosphoglycerate dehydrogenase (PHGDH), inhibiting serine synthesis. This discovery reveals a new cancer therapy target: the ASS1/PHGDH pathway.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Argininosuccinate synthase (ASS1) is a urea cycle enzyme with known tumor suppressor functions in various cancers.
  • The precise anticancer mechanisms of ASS1 remain incompletely understood.
  • Phosphoglycerate dehydrogenase (PHGDH) is a key enzyme regulating serine biosynthesis.

Purpose of the Study:

  • To elucidate the anticancer mechanism of ASS1.
  • To investigate the interaction between ASS1 and PHGDH.
  • To determine the role of the ASS1-PHGDH axis in tumorigenesis and serine metabolism.

Main Methods:

  • Co-immunoprecipitation assays to confirm ASS1-PHGDH interaction.
  • Western blotting to assess protein levels and ubiquitination.
  • Gene knockout and knockdown experiments (CRISPR/Cas9, siRNA).
  • Cell proliferation assays under nutrient-depleted conditions.

Main Results:

  • ASS1 directly binds to PHGDH, promoting its ubiquitination and subsequent degradation.
  • Inhibition of serine synthesis by ASS1 was confirmed, leading to suppressed tumorigenesis.
  • PHGDH knockout abrogated the tumor-suppressive effects of ASS1.
  • ASS1 modulation affected cell proliferation, which was rescued by serine and glycine supplementation.

Conclusions:

  • ASS1 functions as a tumor suppressor by targeting PHGDH for degradation, thereby inhibiting serine synthesis.
  • The ASS1/PHGDH interaction represents a novel regulatory axis in cancer.
  • Targeting the ASS1/PHGDH serine synthesis pathway offers a potential therapeutic strategy for cancer treatment.

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