Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation

Bulusu, Vinay; Tumanov, Sergey; Michalopoulou, Evdokia; Broek, Niels J. van den; Mackay, Gillian; Nixon, Colin; Dhayade, Sandeep; Schug, Zachary T.; Voorde, Johan Vande; Blyth, Karen; Gottlieb, Eyal; Vázquez, Alexei; Kamphorst, Jurre J.

doi:10.1016/j.celrep.2016.12.055

Cited by 217 publications

(223 citation statements)

References 32 publications

(65 reference statements)

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“…5g and 5h) and isotope tracing with deuterated acetaldehyde confirmed that ACLY knockdown cells exhibited increased acetate utilization which could be further increased by limiting nutrient availability during serum starvation (Fig. 5i), which is consistent with previous findings 10,34 . Thus these experiments confirm that de novo pyruvate-derived acetate production can have critical functional roles in supporting acetyl-CoA metabolism.…”

Section: Resultssupporting

confidence: 91%

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: 91%

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

Liu

et al. 2018

Preprint

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“…Acetate can rescue global histone acetylation in the absence of ACLY (Wellen et al, 2009; Zhao et al, 2016), though use of exogenous acetate for histone acetylation is somewhat inefficient (Bulusu et al, 2017; Zhao et al, 2016), suggesting that ACLY- and ACSS2-generated acetyl-CoA might be differentially used in specific contexts. Silencing of ACSS2 had no significant impact on BRCA1 foci formation (Figure S2F).…”

Section: Resultsmentioning

confidence: 99%

Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination

et al. 2017

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SUMMARY While maintaining the integrity of the genome and sustaining bioenergetics are both fundamental functions of the cell, potential crosstalk between metabolic and DNA repair pathways is poorly understood. Since histone acetylation plays important roles in DNA repair and is sensitive to the availability of acetyl-CoA, we investigated a role for metabolic regulation of histone acetylation during the DNA damage response. In this study, we report that nuclear ATP-citrate lyase (ACLY) is phosphorylated at S455 downstream of ATM and AKT following DNA damage. ACLY facilitates histone acetylation at double strand break (DSB) sites, impairing 53BP1 localization and enabling BRCA1 recruitment and DNA repair by homologous recombination. ACLY phosphorylation and nuclear localization are necessary for its role in promoting BRCA1 recruitment. Upon PARP inhibition, ACLY silencing promotes genomic instability and cell death. Thus, the spatial and temporal control of acetyl-CoA production by ACLY participates in the mechanism of DNA repair pathway choice.

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“…ACSS2 is essential for protein acetylation by producing acetyl CoA, which has an important role in many biological processes. ACSS2 can increase histone H3 acetylation in specific regions, which is vital to autophagy, cell survival and tumourigenesis [28,29]. In particular, previous studies have shown that ACSS2 can promote brain carcinogenesis by increasing the expression of autophagy-related factors, such as LAMP1.…”

Section: Cellular Physiology and Biochemistry Cellular Physiology Andmentioning

confidence: 99%

Acetyl-CoA Synthetase 2 Promotes Cell Migration and Invasion of Renal Cell Carcinoma by Upregulating Lysosomal-Associated Membrane Protein 1 Expression

Guo

Gui

2018

Cell Physiol Biochem

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Background/Aims: Reprogramming energy metabolism is an emerging hallmark of many cancers, and this alteration is especially evident in renal cell carcinomas (RCCs). However, few studies have been conducted on lipid metabolism. This study investigated the function and mechanism of lipid metabolism-related acetyl-CoA synthetase 2 (ACSS2) in RCC development, cell migration and invasion. Methods: Quantitative real-time PCR (qRT-PCR) was used to determine the expression of ACSS2 in cancer tissue and adjacent tissue. The inhibition of ACSS2 expression was achieved by RNA interference, which was confirmed by qRT-PCR and Western blotting. Cell proliferation and apoptosis were detected by a CCK8 assay and a flow cytometry analysis, respectively. Cell migration and invasion were determined by the scratch and transwell assays. Following the knockdown of ACSS2 expression, the expression of the autophagy-related factor LAMP1 was measured by qRT-PCR and Western blotting. Results: Compared to adjacent tissues, ACSS2 expression was upregulated in RCC cancer tissues and positively correlated with metastasis. Inhibition of ACSS2 had no effect on RCC cell proliferation or apoptosis. However, decreased ACSS2 expression was found to inhibit RCC cell migration and invasion. ACSS2 was determined to promote the expression of LAMP1, which can also promote cell migration. This pathway may be considered a potential mechanism through which ACSS2 participates in RCC development. Conclusion: These data suggest that ACSS2 is an important factor for promoting RCC development and is essential for cell migration and invasion, which it promotes by increasing the expression of LAMP1. Taken together, these findings reveal a potential target for the diagnosis and treatment of RCC.

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Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation

Cited by 217 publications

References 32 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

Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination

Acetyl-CoA Synthetase 2 Promotes Cell Migration and Invasion of Renal Cell Carcinoma by Upregulating Lysosomal-Associated Membrane Protein 1 Expression

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