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
Affiliations
Xingyao Li
Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
Daniel Gracilla
Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
Lun Cai
Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
Mingyi Zhang
Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Institute of Materia Medica, Peking Union Medical College, Beijing 100050, China
Xiaolin Yu
Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
Xiaoguang Chen
Institute of Materia Medica, Peking Union Medical College, Beijing 100050, China
Junran Zhang
Department of Radiation Oncology, Ohio State University James Comprehensive Cancer Center and College of Medicine, Columbus, OH 43210, USA
Xiaochun Long
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Han-Fei Ding
Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Chunhong Yan
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; Corresponding author
Summary: 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.
