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

doi:10.1016/j.celrep.2021.109706

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 journal › Article › peer-review

7 Scopus citations

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 language	English (US)
Article number	109706
Journal	Cell Reports
Volume	36
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2021.109706
State	Published - 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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10.1016/j.celrep.2021.109706

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@article{4f39f0a01aee46a98a3a99dec461dc55,

title = "ATF3 promotes the serine synthesis pathway and tumor growth under dietary serine restriction",

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",

author = "Xingyao Li and Daniel Gracilla and Lun Cai and Mingyi Zhang and Xiaolin Yu and Xiaoguang Chen and Junran Zhang and Xiaochun Long and Ding, {Han Fei} and Chunhong Yan",

note = "Funding Information: This work was supported by the NIH grants to C.Y. ( R01CA139107 and R01CA240966 ), H.-F.D. ( R01CA190429 and R01CA236890 ), and X. Long ( R01HL122686 and R01HL139794 ), as well as the US Department of Defense award W81XWH1910587 (to C.Y.). We thank the Georgia Cancer Center Integrated Genomics Core for providing the RNA-seq service and the West Coast Metabolomics Core for the metabolomics assays. Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = sep,

day = "21",

doi = "10.1016/j.celrep.2021.109706",

language = "English (US)",

volume = "36",

journal = "Cell Reports",

issn = "2211-1247",

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TY - JOUR

T1 - ATF3 promotes the serine synthesis pathway and tumor growth under dietary serine restriction

AU - Li, Xingyao

AU - Gracilla, Daniel

AU - Cai, Lun

AU - Zhang, Mingyi

AU - Yu, Xiaolin

AU - Chen, Xiaoguang

AU - Zhang, Junran

AU - Long, Xiaochun

AU - Ding, Han Fei

AU - Yan, Chunhong

N1 - Funding Information: This work was supported by the NIH grants to C.Y. ( R01CA139107 and R01CA240966 ), H.-F.D. ( R01CA190429 and R01CA236890 ), and X. Long ( R01HL122686 and R01HL139794 ), as well as the US Department of Defense award W81XWH1910587 (to C.Y.). We thank the Georgia Cancer Center Integrated Genomics Core for providing the RNA-seq service and the West Coast Metabolomics Core for the metabolomics assays. Publisher Copyright: © 2021 The Author(s)

PY - 2021/9/21

Y1 - 2021/9/21

N2 - 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.

AB - 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.

KW - ATF3

KW - ATF4

KW - PHGDH

KW - PSAT1

KW - PSPH

KW - p300

KW - serine biosynthesis

KW - serine deprivation

KW - serine metabolism

KW - serine synthesis pathway

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U2 - 10.1016/j.celrep.2021.109706

DO - 10.1016/j.celrep.2021.109706

M3 - Article

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AN - SCOPUS:85115313030

SN - 2211-1247

VL - 36

JO - Cell Reports

JF - Cell Reports

IS - 12

M1 - 109706

ER -

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

Abstract

Keywords

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