Dietary glutamine supplementation suppresses epigenetically-activated oncogenic pathways to inhibit melanoma tumour growth

Gabra, Mari B. Ishak; Yang, Ying; Li, Haiqing; Senapati, Parijat; Hanse, Eric A.; Lowman, Xazmin H.; Tran, Trac D.; Zhang, Lishi; Doan, Linda; Xu, Xiangdong; Schones, Dustin E.; Fruman, David A.; Kong, Mei

doi:10.1038/s41467-020-17181-w

Cited by 72 publications

(63 citation statements)

References 54 publications

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“…Interestingly, Ishak Gabra et al reported that dietary glutamine supplementation inhibited melanoma tumor growth by suppressing epigenetically activated oncogenic pathways (93). The inhibitory effect of glutamine in tumor growth observed here is due to the elevated intra-tumoral a-KG level, consistent with the reported role of a-KG as a tumor suppressor (94,95).…”

Section: Opposite Roles Of Gls1 and Gls2 In Tumorigenesissupporting

confidence: 88%

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

et al. 2020

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Metabolism rewiring is an important hallmark of cancers. Being one of the most abundant free amino acids in the human blood, glutamine supports bioenergetics and biosynthesis, tumor growth, and the production of antioxidants through glutaminolysis in cancers. In glutamine dependent cancer cells, more than half of the tricarboxylic/critic acid (TCA) metabolites are derived from glutamine. Glutaminolysis controls the process of converting glutamine into TCA cycle metabolites through the regulation of multiple enzymes, among which the glutaminase shows the importance as the very first step in this process. Targeting glutaminolysis via glutaminase inhibition emerges as a promising strategy to disrupt cancer metabolism and tumor progression. Here, we review the regulation of glutaminase and the role of glutaminase in cancer metabolism and metastasis. Furthermore, we highlight the glutaminase inhibitor based metabolic therapy strategy and their potential applications in clinical scenarios.

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Section: Opposite Roles Of Gls1 and Gls2 In Tumorigenesissupporting

confidence: 88%

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

et al. 2020

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“…While the above studies manipulated glutamine levels in vitro, heterogeneity in glutamine availability may also be an important determinant of cell fate in vivo. For example, glutamine deficiency in melanoma cores is sufficient to deplete αKG and blunt cancer cell differentiation and increasing dietary glutamine increases αKG levels and impairs tumorigenesis [10,66]. Altogether, these data are consistent with glutamine availability creating a permissive environment for cell fate determination by enabling αKG accumulation.…”

Section: Amino Acidssupporting

confidence: 54%

Metabolic Coordination of Cell Fate by α-Ketoglutarate-Dependent Dioxygenases

Baksh

Finley

2021

Trends in Cell Biology

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Cell fate determination requires faithful execution of gene expression programs, which are increasingly recognized to respond to metabolic inputs. In particular, the family of α-ketoglutarate (αKG)-dependent dioxygenases, which include several chromatin-modifying enzymes, are emerging as key mediators of metabolic control of cell fate. αKG-dependent dioxygenases consume the metabolite αKG (also known as 2-oxoglutarate) as an obligate cosubstrate and are inhibited by succinate, fumarate, and 2-hydroxyglutarate. Here, we review the role of these metabolites in the control of dioxygenase activity and cell fate programs. We discuss the biochemical and transcriptional mechanisms enabling these metabolites to control cell fate and review evidence that nutrient availability shapes tissue-specific fate programs via αKG-dependent dioxygenases. Cell Fate Determination Responds to Metabolic Inputs Development and homeostasis of multicellular organisms depends on cells acquiring and maintaining the correct fate at the right place and time. Cell fate determination (see Glossary), wherein less differentiated cells progressively acquire specific fates and functions, is essential for proper embryogenesis and maintenance of postnatal tissue homeostasis by stem cells. In both the embryo and postnatal tissues, cell fate determination depends both on inductive signals from the environment and the competence of cells to respond appropriately to these signals [1,2]. Accordingly, dysregulation of either extracellular cues or their downstream intracellular responses compromise cell fate programs and results in diseases ranging from birth defects to cancer [1,2]. Consequently, dissecting the molecular regulation of cell fate decisions is critically important for understanding the mechanistic basis of both normal physiology and disease states. Increasingly, metabolites are recognized as important modulators of the regulatory programs that control cell fate. In particular, chemical modifications on DNA and histones provide a critical avenue for cells to control activation of gene expression programs that specify cell identity [3]. These chemical modifications are derived from intermediates of cellular metabolism, most notably S-adenosylmethionine and acetyl-CoA, which serve as the donors for methylation and acetylation modifications, respectively. Enzymes that remove these modifications often also require metabolites as critical cosubstrates. Accordingly, fluctuations in the availability of key metabolites that modulate activity of chromatin-modifying enzymes are postulated to contribute to transcriptional regulation by shaping the chromatin landscape [4]. Intracellular metabolite levels are responsive to both cell-intrinsic metabolic pathway activity as well as extrinsic cues from the microenvironment, including growth factors and nutrient availability. Many inputs, including tissue lineage, proliferative status, and nutrient availability, collectively determine the metabolic demands of individual cells [5]. In turn, cell type-specific me...

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“…Similar results were reported by Pan et al 36 during glutamine starvation. Additional report by Gabra et al demonstrated that in melanoma, intratumoral glutamine-dependent αKG regulates the level of H3K4me3 37 . The differential effects of lysine demethylases on histones could be due to their differential affinities toward αKG.…”

Section: Discussionmentioning

confidence: 92%

Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes

Hsu¹,

Chen²,

Cheng³

et al. 2021

Theranostics

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Rationale : One of the most common metabolic defects in cancers is the deficiency in arginine synthesis, which has been exploited therapeutically. Yet, challenges remain, and the mechanisms of arginine-starvation induced killing are largely unclear. Here, we sought to demonstrate the underlying mechanisms by which arginine starvation-induced cell death and to develop a dietary arginine-restriction xenograft model to study the in vivo effects. Methods : Multiple castration-resistant prostate cancer cell lines were treated with arginine starvation followed by comprehensive analysis of microarray, RNA-seq and ChIP-seq were to identify the molecular and epigenetic pathways affected by arginine starvation. Metabolomics and Seahorse Flux analyses were used to determine the metabolic profiles. A dietary arginine-restriction xenograft mouse model was developed to assess the effects of arginine starvation on tumor growth and inflammatory responses. Results : We showed that arginine starvation coordinately and epigenetically suppressed gene expressions, including those involved in oxidative phosphorylation and DNA repair, resulting in DNA damage, chromatin-leakage and cGAS-STING activation, accompanied by the upregulation of type I interferon response. We further demonstrated that arginine starvation-caused depletion of α-ketoglutarate and inactivation of histone demethylases are the underlying causes of epigenetic silencing. Significantly, our dietary arginine-restriction model showed that arginine starvation suppressed prostate cancer growth in vivo , with evidence of enhanced interferon responses and recruitment of immune cells. Conclusions : Arginine-starvation induces tumor cell killing by metabolite depletion and epigenetic silencing of metabolic genes, leading to DNA damage and chromatin leakage. The resulting cGAS-STING activation may further enhance these killing effects.

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Dietary glutamine supplementation suppresses epigenetically-activated oncogenic pathways to inhibit melanoma tumour growth

Cited by 72 publications

References 54 publications

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

Metabolic Coordination of Cell Fate by α-Ketoglutarate-Dependent Dioxygenases

Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes

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