Lineage-Specific Silencing of <i>PSAT1</i> Induces Serine Auxotrophy and Sensitivity to Dietary Serine Starvation in Luminal Breast Tumors

Choi, Byungjoo; Conger, Kelly O.; Selfors, Laura M.; Coloff, Jonathan L.

doi:10.1101/2020.06.19.161844

Cited by 3 publications

(4 citation statements)

References 53 publications

(50 reference statements)

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“…The first enzyme in the de novo serine synthesis pathway (SSP)-phosphoglycerate dehydrogenase (PHGDH) is found up-regulated in melanoma and breast cancers through genomic amplification by increasing the copy number of the gene, which adequately support cancer cell growth in the absence of serine (93,94). The expression of another SSP enzyme phosphoserine aminotransferase (PSAT), which is downstream of PHGDH, also has a decisive role in terms of controlling serine dependency in breast tumors (95). Therefore, insufficient synthesis and increased demand of serine during tumor growth make the extracellular serine supply become a limiting factor that suppresses tumor development in various contexts.…”

Section: Serinementioning

confidence: 99%

“…Low levels of methionine synthase (MS) or deletion of methylthioadenosine phosphorylase (MTAP) which salvage methionine through polyamine metabolism could explain methionine dependence (62,149). Blocking serine synthesis pathway through silencing PSAT causes serine auxotrophy in luminal breast tumors (95). By contrast, functional supply of nutrients from de novo synthesis readily supports tumor growth under limiting conditions.…”

Section: Deficiency or Insufficiency In De Novo Or Salvage Synthesismentioning

confidence: 99%

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Targeting Nutrient Dependency in Cancer Treatment

Fan

Li²,

Gao

et al. 2022

Front. Oncol.

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Metabolic reprogramming is one of the hallmarks of tumor. Growing evidence suggests metabolic changes that support oncogenic progression may cause selective vulnerabilities that can be exploited for cancer treatment. Increasing demands for certain nutrients under genetic determination or environmental challenge enhance dependency of tumor cells on specific nutrient, which could be therapeutically developed through targeting such nutrient dependency. Various nutrients including several amino acids and glucose have been found to induce dependency in genetic alteration- or context-dependent manners. In this review, we discuss the extensively studied nutrient dependency and the biological mechanisms behind such vulnerabilities. Besides, existing applications and strategies to target nutrient dependency in different cancer types, accompanied with remaining challenges to further exploit these metabolic vulnerabilities to improve cancer therapies, are reviewed.

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Section: Serinementioning

confidence: 99%

Section: Deficiency or Insufficiency In De Novo Or Salvage Synthesismentioning

confidence: 99%

Targeting Nutrient Dependency in Cancer Treatment

Fan

Li²,

Gao

et al. 2022

Front. Oncol.

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“…The copyright holder for this preprint this version posted September 6, 2021. ; https://doi.org/10.1101/2021.09.05.459037 doi: bioRxiv preprint 4 lines 18 . These observations raise the intriguing possibility that a common driver may underlie the simultaneous gain of serine synthesis pathway and ER silencing in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

“…At the molecular level, serine starvation diverts glucose carbons to de novo serine synthesis while upregulating the key serine synthesis enzymes phosphoglycerate dehydrogenase (PHGDH), phosphoserine amino transferase (PSAT1), and phosphoserine phosphatase (PSPH) 16 . Intriguingly, PHGDH is upregulated in about 70% of ER - breast cancers compared to ER + tumors 17 , and luminal breast cancer cell lines tend to be more auxotrophic for serine compared to basal-like breast cancer cell lines 18 . These observations raise the intriguing possibility that a common driver may underlie the simultaneous gain of serine synthesis pathway and ER silencing in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Serine Starvation Silences Estrogen Receptor Signaling through Histone Hypoacetylation

et al. 2021

Preprint

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Estrogen receptor (ER) plays important roles in regulating normal development and female reproductive system function. Loss of ER pathway activity is a hallmark of breast cancer progression, associated with accelerated tumor proliferation and resistance to endocrine therapy. How ER loss occurs remains poorly understood. Here, we show that serine starvation, a metabolic stress often found in solid tumors, downregulates estrogen receptor alpha (ERα) expression, represses transcriptional targets such as progesterone receptor (PR), and reduces sensitivity to antiestrogens, suggesting a transition of ER-positive (ER+) breast cancer cells to an ER/PR-negative (ER-/PR-) state. ER downregulation under serine starvation is accompanied by a global loss of histone acetylation. These chromatin changes are driven by metabolic reprogramming triggered by serine starvation, particularly lower glucose flux through glycolysis and the TCA cycle, leading to reduced acetyl-CoA levels and histone hypoacetylation. Supplementation with acetate or glycerol triacetate (GTA), precursors of acetyl-CoA, restores H3K27 acetylation and ERα expression under serine starvation. Therefore, a major consequence of serine starvation in breast cancer could be global chromatin changes that influence lineage-specific gene expression.

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Phosphoserine Aminotransferase 1: A Metabolic Enzyme Target of Cancers

Chen

Yang

2023

CCDT

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Phosphoserine aminotransferase 1 (PSAT1) catalyzes 3-phosphohydroxylpyruvate and glutamate into 3-phosphoserine and α-ketoglutamate. It integrates metabolic pathways critical for cell proliferation, survival, migration and epigenetics, such as glycolysis, de novo serine synthesis, citric acid cycle and one-carbon metabolism. The level of this enzyme has been disclosed to be closely related to the occurrence, progression and prognosis of cancers like non-small cell lung cancer, colorectal cancer, esophageal squamous cell carcinoma, breast cancer, etc. Via metabolic catalyzation, PSAT1 offers anabolic and energic supports for these tumor cells, affecting their proliferation, survival, authophagy, migration and invasion. Such functions even influence epigenetics of other noncancerous cells and drive them to serve tumor cells. Moreover, PSAT1 exerts non-enzymatic regulation of IGF1 pathway and nuclear PKM2 to promote EMT and cancer metastasis. Genetically manipulating PSAT1 alters tumor progression in vitro and in vivo. This paper reviews the role and action mechanism of PSAT1 in tumor biology and chemotherapy as well as the regulation of PSAT1 expression , exhibiting the perspective for PSAT1 as a new molecular marker and target for cancer diagnosis and treatment.

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Lineage-Specific Silencing of PSAT1 Induces Serine Auxotrophy and Sensitivity to Dietary Serine Starvation in Luminal Breast Tumors

Cited by 3 publications

References 53 publications

Targeting Nutrient Dependency in Cancer Treatment

Targeting Nutrient Dependency in Cancer Treatment

Serine Starvation Silences Estrogen Receptor Signaling through Histone Hypoacetylation

Phosphoserine Aminotransferase 1: A Metabolic Enzyme Target of Cancers

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