Akt-Dependent Metabolic Reprogramming Regulates Tumor Cell Histone Acetylation

Lee, Joyce V.; Carrer, Alessandro; Shah, Supriya; Snyder, Nathaniel W.; Wei, Shuanzeng; Venneti, Sriram; Worth, Andrew J.; Yuan, Zuo Fei; Lim, Hee‐Woong; Liu, Shichong; Jackson, Ellen; Aiello, Nicole M.; Haas, Naomi B.; Rebbeck, Timothy R.; Judkins, Alexander R.; Won, Kyoung Jae; Chodosh, Lewis A.; García, Benjamin A.; Stanger, Ben Z.; Feldman, Michael D.; Blair, Ian A.; Wellen, Kathryn E.

doi:10.1016/j.cmet.2014.06.004

Cited by 465 publications

(493 citation statements)

References 55 publications

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“…Possibly, other thiol-containing molecules, such as GSH could serve as the acetyl group acceptor, considering that the cellular CoA is around 10 µM while GSH is 1 to 7 mM (Fig. 3b), and similar concentration values in different types of cells or tissues were also reported by others [28][29][30] . Low levels of CoA and high levels of GSH were also observed in autochthonous mouse tumors providing a physiological context for this occurrence (Fig.…”

Section: Resultssupporting

confidence: 82%

De novo acetate production is coupled to central carbon metabolism in mammals

Liu

et al. 2018

Preprint

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In cases of nutritional excess, there is incomplete catabolism of a nutritional source and secretion of a waste product (overflow metabolism), such as the conversion of glucose to lactate (the Warburg Effect) in tumors. Here we report that excess glucose metabolism generates acetate, a key nutrient whose source has been unclear. Conversion of pyruvate, the product of glycolysis, to acetate occurs through two mechanisms: 1) coupling to reactive oxygen species (ROS), and 2) a neomorphic enzyme activity from keto acid dehydrogenases that enable it to function as a pyruvate decarboxylase. Furthermore, we demonstrate that glucose-derived acetate is sufficient to maintain acetyl-coenzyme A (Ac-CoA) pools and cell proliferation in certain limited metabolic environments such as during mitochondrial dysfunction or ATP citrate lyase (ACLY) deficiency. Thus, de novo acetate production is coupled to the activity of central carbon metabolism providing possible regulatory mechanisms and links to pathophysiology.peer-reviewed)

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Section: Resultssupporting

confidence: 82%

De novo acetate production is coupled to central carbon metabolism in mammals

Liu

et al. 2018

Preprint

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“…Combined with the observation that free CoA is present at roughly equimolar concentrations to acetyl-CoA in cells (Gao et al, 2007;Lee et al, 2014), it is plausible that the ratio of acetyl-CoA to CoA may modulate KAT activity (Albaugh et al, 2011). Interestingly, a recent study profiling the acyl chain specificity of Gcn5 observed potent inhibition by long fatty acyl-CoA molecules like palmitoyl-CoA (Montgomery et al), further supporting the idea that acyl-CoA molecules may function as natural KAT inhibitors.…”

Section: Discussionmentioning

confidence: 88%

“…As a result, intracellular concentrations of different acyl-CoA species change in response to metabolic fluctuations (Hosokawa et al, 1986;Palladino et al, 2012;King & Reiss, 1985). For example, measurements of the intracellular concentration of acetyl-CoA vary based on nutrient availability, and range from 3 to 30 µM in yeast (Cai et al, 2011;Weinert, 2014) and 2 to 13 µM in human cells (Lee et al, 2014). With a K m for acetyl-CoA of 0.91 ± 0.09 µM (Figure 5A), acetyl-CoA availability may regulate the activity of human Gcn5 (Albaugh et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Structural basis for acyl group discrimination by human Gcn5L2

Ringel

Wolberger

2016

Preprint

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Gcn5 is a conserved acetyltransferase that regulates transcription by acetylating the Nterminal tails of histones. Motivated by recent studies identifying a chemically diverse array of lysine acyl modifications in vivo, we examined the acyl chain specificity of the acetyltransferase, human Gcn5 (Gcn5L2). Whereas Gcn5L2 robustly catalyzes lysine acetylation, the acyltransferase activity of Gcn5L2 gets progressively weaker with increasing acyl chain length. To understand how Gcn5 discriminates between different acyl-CoA molecules, we determined structures of the catalytic domain of human Gcn5L2 bound to propionyl-CoA and butyryl-CoA. Although the active site of Gcn5L2 can accommodate propionyl-CoA and butyryl-CoA without major structural rearrangements, butyryl-CoA adopts a conformation incompatible with catalysis that obstructs the path of the incoming lysine residue and acts as a competitive inhibitor for Gcn5L2 versus acetyl-CoA. These structures demonstrate how Gcn5L2 discriminates between acyl chain donors and explain why Gcn5L2 has weak activity for acyl moieties that are larger than an acetyl group.

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“…47,48 The starvation-induced reduction in IGF1 bioavailability would reduce the AKT1 (AKT serine/threonine kinase 1)-dependent activity of the acetyl-CoA-generating enzyme ACLY (ATP citrate lyase). 49 If a reduced flux in acetyl-CoA production was linked to immediate deacetylation, then the acetate generated as a result of histone deacetylation would cause an immediate increase in free acetate, which in turn would constitute a source for acetyl-CoA, hence maintaining stable acetyl-CoA levels. 50,51 Nonetheless, this hypothetical conjecture requires further exploration.…”

Section: Discussionmentioning

confidence: 99%

Metabolic effects of fasting on human and mouse blood in vivo

et al. 2017

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Starvation is a strong physiological stimulus of macroautophagy/autophagy. In this study, we addressed the question as to whether it would be possible to measure autophagy in blood cells after nutrient deprivation. Fasting of mice for 48 h (which causes »20% weight loss) or starvation of human volunteers for up to 4 d (which causes <2% weight loss) provokes major changes in the plasma metabolome, yet induces only relatively minor alterations in the intracellular metabolome of circulating leukocytes. White blood cells from mice and human volunteers responded to fasting with a marked reduction in protein lysine acetylation, affecting both nuclear and cytoplasmic compartments. In circulating leukocytes from mice that underwent 48-h fasting, an increase in LC3B lipidation (as assessed by immunoblotting and immunofluorescence) only became detectable if the protease inhibitor leupeptin was injected 2 h before drawing blood. Consistently, measurement of an enhanced autophagic flux was only possible if white blood cells from starved human volunteers were cultured in the presence or absence of leupeptin. Whereas all murine leukocyte subpopulations significantly increased the number of LC3B C puncta per cell in response to nutrient deprivation, only neutrophils from starved volunteers showed signs of activated autophagy (as determined by a combination of multi-color immunofluorescence, cytofluorometry and image analysis). Altogether, these results suggest that white blood cells are suitable for monitoring autophagic flux. In addition, we propose that the evaluation of protein acetylation in circulating leukocytes can be adopted as a biochemical marker of organismal energetic status.

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Akt-Dependent Metabolic Reprogramming Regulates Tumor Cell Histone Acetylation

Cited by 465 publications

References 55 publications

De novo acetate production is coupled to central carbon metabolism in mammals

De novo acetate production is coupled to central carbon metabolism in mammals

Structural basis for acyl group discrimination by human Gcn5L2

Metabolic effects of fasting on human and mouse blood in vivo

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