ATF3 promotes the serine synthesis pathway and tumor growth under dietary serine restriction

Xingyao Li, Daniel Gracilla, Lun Cai, Mingyi Zhang, Xiaolin Yu, Xiaoguang Chen, Junran Zhang, Xiaochun Long, Han Fei Ding, Chunhong Yan

Research output: Contribution to journalArticlepeer-review

Abstract

The serine synthesis pathway (SSP) involving metabolic enzymes phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) drives intracellular serine biosynthesis and is indispensable for cancer cells to grow in serine-limiting environments. However, how SSP is regulated is not well understood. Here, we report that activating transcription factor 3 (ATF3) is crucial for transcriptional activation of SSP upon serine deprivation. ATF3 is rapidly induced by serine deprivation via a mechanism dependent on ATF4, which in turn binds to ATF4 and increases the stability of this master regulator of SSP. ATF3 also binds to the enhancers/promoters of PHGDH, PSAT1, and PSPH and recruits p300 to promote expression of these SSP genes. As a result, loss of ATF3 expression impairs serine biosynthesis and the growth of cancer cells in the serine-deprived medium or in mice fed with a serine/glycine-free diet. Interestingly, ATF3 expression positively correlates with PHGDH expression in a subset of TCGA cancer samples.

Original languageEnglish (US)
Article number109706
JournalCell Reports
Volume36
Issue number12
DOIs
StatePublished - Sep 21 2021

Keywords

  • ATF3
  • ATF4
  • PHGDH
  • PSAT1
  • PSPH
  • p300
  • serine biosynthesis
  • serine deprivation
  • serine metabolism
  • serine synthesis pathway

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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