2. Academic Validation
  3. ATF3 promotes the serine synthesis pathway and tumor growth under dietary serine restriction

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

  • Cell Rep. 2021 Sep 21;36(12):109706. doi: 10.1016/j.celrep.2021.109706.
Xingyao Li 1,  Daniel Gracilla 1,  Lun Cai 1,  Mingyi Zhang 2,  Xiaolin Yu 1,  Xiaoguang Chen 3,  Junran Zhang 4,  Xiaochun Long 5,  Han-Fei Ding 6,  Chunhong Yan 7
Affiliations

Affiliations

  • 1 Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
  • 2 Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Institute of Materia Medica, Peking Union Medical College, Beijing 100050, China.
  • 3 Institute of Materia Medica, Peking Union Medical College, Beijing 100050, China.
  • 4 Department of Radiation Oncology, Ohio State University James Comprehensive Cancer Center and College of Medicine, Columbus, OH 43210, USA.
  • 5 Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
  • 6 Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
  • 7 Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. Electronic address: cyan@augusta.edu.
PMID: 34551291 DOI: 10.1016/j.celrep.2021.109706
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.

Keywords

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

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