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
  • 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: [email protected].
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.