scholarly journals Mammalian SIRT6 Represses Invasive Cancer Cell Phenotypes through ATP Citrate Lyase (ACLY)-Dependent Histone Acetylation

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1460
Author(s):  
Wei Zheng ◽  
Luisa Tasselli ◽  
Tie-mei Li ◽  
Katrin F. Chua
Keyword(s):  
Gene Expression ◽  
Histone Acetylation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Invasive Cancer ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Citrate Lyase ◽  
Cell Phenotypes ◽  
Invasive Cancer Cell

The modulation of dynamic histone acetylation states is key for organizing chromatin structure and modulating gene expression and is regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes. The mammalian SIRT6 protein, a member of the Class III HDAC Sirtuin family of NAD+-dependent enzymes, plays pivotal roles in aging, metabolism, and cancer biology. Through its site-specific histone deacetylation activity, SIRT6 promotes chromatin silencing and transcriptional regulation of aging-associated, metabolic, and tumor suppressive gene expression programs. ATP citrate lyase (ACLY) is a nucleo-cytoplasmic enzyme that produces acetyl coenzyme A (acetyl-CoA), which is the required acetyl donor for lysine acetylation by HATs. In addition to playing a central role in generating cytosolic acetyl-CoA for de novo lipogenesis, a growing body of work indicates that ACLY also functions in the nucleus where it contributes to the nutrient-sensitive regulation of nuclear acetyl-CoA availability for histone acetylation in cancer cells. In this study, we have identified a novel function of SIRT6 in controlling nuclear levels of ACLY and ACLY-dependent tumor suppressive gene regulation. The inactivation of SIRT6 in cancer cells leads to the accumulation of nuclear ACLY protein and increases nuclear acetyl-CoA pools, which in turn drive locus-specific histone acetylation and the expression of cancer cell adhesion and migration genes that promote tumor invasiveness. Our findings uncover a novel mechanism of SIRT6 in suppressing invasive cancer cell phenotypes and identify acetyl-CoA responsive cell migration and adhesion genes as downstream targets of SIRT6.

Abstract 15978: Acetyl-coa Catalysis by Atp-citrate Lyase is Essential for Myofibroblast Differentiation and Persistence

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Michael P Lazaropoulos ◽  
Andrew A Gibb ◽  
Anh Huynh ◽  
Kathryn Wellen ◽  
John W Elrod
Keyword(s):  
Histone Acetylation ◽  
Transcriptional Activation ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Metabolic Reprogramming ◽  
Myofibroblast Differentiation ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Matrix Deposition ◽  
Citrate Lyase

A feature of heart failure (HF) is excessive extracellular matrix deposition and cardiac remodeling by a differentiated fibroblast population known as myofibroblasts. Identifying mechanisms of myofibroblast differentiation in cardiac fibrosis could yield novel therapeutic targets to delay or reverse HF. Recent evidence suggests that myofibroblast differentiation requires metabolic reprogramming for transcriptional activation of the myofibroblast gene program by chromatin-dependent mechanisms. We previously reported that inhibition of histone demethylation blocks myofibroblast formation, however, whether histone acetylation (e.g., H3K27ac, a prominent mark associated with gene transcription) is involved in fibroblast reprogramming remains unclear. ATP-citrate lyase (ACLY) synthesizes acetyl-CoA and therein supplies acetyl-CoA to the nucleus, where it is used as a substrate by histone acetyltransferases (HATs). To define the role of acetyl-CoA metabolism in myofibroblast differentiation, we stimulated differentiation in mouse embryonic fibroblasts (MEFs) and adult mouse cardiac fibroblasts (ACFs) with the pro-fibrotic agonist transforming growth factor β (TGFβ) and treated cells with a pharmacological inhibitor of ACLY. ACLY inhibition decreased myofibroblast gene expression in ACF and MEFs in TGFβ-stimulated myofibroblast differentiation, in addition to decreasing the population of αSMA positive MEFs. Genetic deletion of ACLY in MEFs recapitulated the results observed with pharmacological inhibition. Encouragingly, the ACLY inhibitor was sufficient to revert fully differentiated myofibroblasts under continuous TGFβ stimulation to a quiescent, non-fibrotic phenotype. Altogether, our data indicate that ACLY activity is necessary for myofibroblast differentiation and persistence. We hypothesize that ACLY-dependent acetyl-CoA synthesis is necessary for histone acetylation and transcriptional activation of the myofibroblast gene program. Currently, we are examining mechanisms of ACLY-dependent chromatin remodeling in fibroblasts and the in vivo relevance of this mechanism in mutant mice. In summary, ACLY is a potential target to reverse cardiac fibrosis and lessen HF.

scholarly journals ATP-citrate lyase is essential for high glucose-induced histone hyperacetylation and fibrogenic gene upregulation in mesangial cells

2017 ◽  
Vol 313 (2) ◽  
pp. F423-F429 ◽  
Author(s):  
Dilip K. Deb ◽  
Yinyin Chen ◽  
Jian Sun ◽  
Youli Wang ◽  
Yan Chun Li
Keyword(s):  
Histone Acetylation ◽  
High Glucose ◽  
Mesangial Cells ◽  
Nuclear Accumulation ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Ecm Proteins ◽  
Histone Hyperacetylation ◽  
Citrate Lyase ◽  
Tgf Β1

The goal of this study was to address the role of ATP-citrate lyase (ACL), an enzyme that converts citrate to acetyl-CoA, in high glucose (HG)-induced histone acetylation and profibrotic gene expression. Our recent ChIP-Seq studies have demonstrated that HG induces genome-wide histone hyperacetylation in mesangial cells (MCs). Here, we showed that exposure of MCs to HG markedly increased histone acetylation at the H3K9/14 and H3K18 marks and induced the expression of potent profibrotic factors TGF-β1, TGF-β3, and connective tissue growth factor (CTGF). The induction of these profibrotic factors was further enhanced by histone deacetylase inhibitor but suppressed by histone acetyl-transferase inhibitor, confirming the importance of histone acetylation in this regulation. Interestingly, HG not only upregulated ACL expression but also promoted ACL nuclear translocation, evidenced by increased ACL concentration and activity in the nuclear extracts. Consistent with this observation, transfection of MCs with a plasmid-carrying green fluorescent protein (GFP)-ACL fusion protein led to GFP nuclear accumulation when cultured in HG condition. Silencing ACL with siRNAs alleviated HG-induced histone hyperacetylation, as well as upregulation of TGF-β1, TGF-β3, CTGF, and extracellular matrix (ECM) proteins fibronectin and collagen type IV, whereas ACL overexpression further enhanced HG induction of histone acetylation, as well as these profibrotic factors and ECM proteins. Collectively, these observations demonstrate that HG promotes ACL expression and translocation into the nucleus, where ACL converts citrate to acetyl-CoA to provide the substrate for histone acetylation, leading to upregulation of fibrogenic genes. Therefore, ACL plays a critical role in epigenetic regulation of diabetic renal fibrosis.

scholarly journals Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression

2018 ◽  
Author(s):  
Oswaldo A. Lozoya ◽  
Tianyuan Wang ◽  
Dagoberto Grenet ◽  
Taylor C. Wolfgang ◽  
Mack Sobhany ◽  
...  
Keyword(s):  
Gene Expression ◽  
Specific Gene ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Mtdna Depletion ◽  
Citrate Lyase ◽  
Environmental Agents ◽  
Physiological Outcomes ◽  
The Impact ◽  
Histone Hypoacetylation

AbstractThe impact of mitochondria in epigenetics is emerging but our understanding of this relationship and its impact on gene expression remain incomplete. We previously showed that acute mitochondrial DNA (mtDNA) loss leads to histone hypoacetylation. It remains to be defined if these changes are maintained when mitochondrial dysfunction is chronic and, importantly, if they are sufficient to alter gene expression. To fill these gaps, we here studied both a progressive and a chronic model of mtDNA depletion using biochemical, pharmacological, genomics and genetic assays. We show that histones are hypoacetylated in both models. We link these effects to decreased histone acetyltransferase (HAT) activity independent of changes in ATP citrate lyase function, which can be reversibly modulated by altering specifically the mitochondrial pool of acetyl-CoA. Also, we determined that these changes regulate locus-specific gene expression and physiological outcomes, including the production of prostaglandins. These results may be relevant to the pathophysiology of mtDNA depletion syndromes and to understanding the effects of environmental agents, such as AZT or antibiotics, that lead to physical or functional mtDNA loss.

scholarly journals The Drosophila Citrate Lyase Is Required for Cell Division during Spermatogenesis

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 206
Author(s):  
Maria Laura Di Giorgio ◽  
Patrizia Morciano ◽  
Elisabetta Bucciarelli ◽  
Antonella Porrazzo ◽  
Francesca Cipressa ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cell Division ◽  
Histone Acetylation ◽  
Male Meiosis ◽  
Metabolic Enzyme ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Alternative Pathways ◽  
Citrate Lyase ◽  
First Time

The Drosophila melanogaster DmATPCL gene encodes for the human ATP Citrate Lyase (ACL) ortholog, a metabolic enzyme that from citrate generates glucose-derived Acetyl-CoA, which fuels central biochemical reactions such as the synthesis of fatty acids, cholesterol and acetylcholine, and the acetylation of proteins and histones. We had previously reported that, although loss of Drosophila ATPCL reduced levels of Acetyl-CoA, unlike its human counterpart, it does not affect global histone acetylation and gene expression, suggesting that its role in histone acetylation is either partially redundant in Drosophila or compensated by alternative pathways. Here, we describe that depletion of DmATPCL affects spindle organization, cytokinesis, and fusome assembly during male meiosis, revealing an unanticipated role for DmATPCL during spermatogenesis. We also show that DmATPCL mutant meiotic phenotype is in part caused by a reduction of fatty acids, but not of triglycerides or cholesterol, indicating that DmATPCL-derived Acetyl-CoA is predominantly devoted to the biosynthesis of fatty acids during spermatogenesis. Collectively, our results unveil for the first time an involvement for DmATPCL in the regulation of meiotic cell division, which is likely conserved in human cells.

scholarly journals Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels

2017 ◽  
Vol 292 (8) ◽  
pp. 3312-3322 ◽  
Author(s):  
Alessandro Carrer ◽  
Joshua L. D. Parris ◽  
Sophie Trefely ◽  
Ryan A. Henry ◽  
David C. Montgomery ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
High Fat Diet ◽  
Cell Types ◽  
High Fat ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Citrate Lyase ◽  
Liver And Pancreas ◽  
The Impact

Cellular metabolism dynamically regulates the epigenome via availability of the metabolite substrates of chromatin-modifying enzymes. The impact of diet on the metabolism-epigenome axis is poorly understood but could alter gene expression and influence metabolic health. ATP citrate-lyase produces acetyl-CoA in the nucleus and cytosol and regulates histone acetylation levels in many cell types. Consumption of a high-fat diet (HFD) results in suppression of ATP citrate-lyase levels in tissues such as adipose and liver, but the impact of diet on acetyl-CoA and histone acetylation in these tissues remains unknown. Here we examined the effects of HFD on levels of acyl-CoAs and histone acetylation in mouse white adipose tissue (WAT), liver, and pancreas. We report that mice consuming a HFD have reduced levels of acetyl-CoA and/or acetyl-CoA:CoA ratio in these tissues. In WAT and the pancreas, HFD also impacted the levels of histone acetylation; in particular, histone H3 lysine 23 acetylation was lower in HFD-fed mice. Genetic deletion of Acly in cultured adipocytes also suppressed acetyl-CoA and histone acetylation levels. In the liver, no significant effects on histone acetylation were observed with a HFD despite lower acetyl-CoA levels. Intriguingly, acetylation of several histone lysines correlated with the acetyl-CoA: (iso)butyryl-CoA ratio in liver. Butyryl-CoA and isobutyryl-CoA interacted with the acetyltransferase P300/CBP-associated factor (PCAF) in liver lysates and inhibited its activity in vitro. This study thus provides evidence that diet can impact tissue acyl-CoA and histone acetylation levels and that acetyl-CoA abundance correlates with acetylation of specific histone lysines in WAT but not in the liver.

Measuring systematic changes in invasive cancer cell shape using Zernike moments

2016 ◽  
Vol 8 (11) ◽  
pp. 1183-1193 ◽  
Author(s):  
Elaheh Alizadeh ◽  
Samanthe Merrick Lyons ◽  
Jordan Marie Castle ◽  
Ashok Prasad
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Cell Shape ◽  
Zernike Moments ◽  
Invasive Cancer ◽  
Two Dimensional ◽  
Dimensional Cell ◽  
Invasive Cancer Cell

Cancer cells show similar changes in two dimensional cell shape analyzed using Zernike moments.

Polyamine regulating protein antizyme binds to ATP citrate lyase to accelerate acetyl-CoA production in cancer cells

2016 ◽  
Vol 471 (4) ◽  
pp. 646-651 ◽  
Author(s):  
Ayasa Tajima ◽  
Noriyuki Murai ◽  
Yasuko Murakami ◽  
Takeo Iwamoto ◽  
Toshiro Migita ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Citrate Lyase

scholarly journals Exploring the Role of ATP-Citrate Lyase in the Immune System

2021 ◽  
Vol 12 ◽  
Author(s):  
Monica Dominguez ◽  
Bernhard Brüne ◽  
Dmitry Namgaladze
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Histone Acetylation ◽  
Epigenetic Regulation ◽  
De Novo ◽  
Regulation Of Gene Expression ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Citrate Lyase

Studies over the past decade have revealed that metabolism profoundly influences immune responses. In particular, metabolism causes epigenetic regulation of gene expression, as a growing number of metabolic intermediates are substrates for histone post-translational modifications altering chromatin structure. One of these substrates is acetyl-coenzyme A (CoA), which donates an acetyl group for histone acetylation. Cytosolic acetyl-CoA is also a critical substrate for de novo synthesis of fatty acids and sterols necessary for rapid cellular growth. One of the main enzymes catalyzing cytosolic acetyl-CoA formation is ATP-citrate lyase (ACLY). In addition to its classical function in the provision of acetyl-CoA for de novo lipogenesis, ACLY contributes to epigenetic regulation through histone acetylation, which is increasingly appreciated. In this review we explore the current knowledge of ACLY and acetyl-CoA in mediating innate and adaptive immune responses. We focus on the role of ACLY in supporting de novo lipogenesis in immune cells as well as on its impact on epigenetic alterations. Moreover, we summarize alternative sources of acetyl-CoA and their contribution to metabolic and epigenetic regulation in cells of the immune system.

scholarly journals The STAT3 inhibitor Stattic acts independently of STAT3 to decrease histone acetylation and modulate gene expression

2020 ◽  
pp. jbc.RA120.016645
Author(s):  
Dipak K. Poria ◽  
Namratha Sheshadri ◽  
Kuppusamy Balamurugan ◽  
Shikha Sharan ◽  
Esta Sterneck
Keyword(s):  
Gene Expression ◽  
Histone Acetylation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Breast Cancer Cell Lines ◽  
Independent Effects

Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor involved in many physiological functions including embryonic development and immune responses and is often activated under pathological conditions such as cancer. Strategies to inactivate STAT3 are being pursued as potential anticancer therapies and have led to the identification of Stattic (6-nitrobenzo(b)thiophene-1,1-dioxide) as a “specific” STAT3 inhibitor that is often used to interrogate STAT3-mediated gene expression in vitro and in vivo.  Here, we show that Stattic exerts many STAT3-independent effects on cancer cells, calling for re-assessment of results previously ascribed to STAT3 functions. Studies of the STAT3-deficient prostate cancer cell line PC3 (PC-3) along with STAT3-proficient breast cancer cell lines (MDA-MB-231, SUM149) revealed that Stattic attenuated histone acetylation and neutralized effects of the histone deacetylase (HDAC) inhibitor romidepsin. In PC3 cells, Stattic alone inhibited gene expression of CCL20 and CCL2, but activated expression of TNFA, CEBPD, SOX2, and MYC. In addition, we found that Stattic promoted autophagy and caused cell death. These data point to profound epigenetic effects of Stattic that are independent of its function as a STAT3 inhibitor. Our results demonstrate that Stattic directly or indirectly reduces histone acetylation and suggest re-evaluation of Stattic and related compounds as polypharmacological agents through multipronged cytotoxic effects on cancer cells.

Acetyl-CoA is produced by the citrate synthase homology module of ATP-citrate lyase

2021 ◽  
Author(s):  
Kenneth Verstraete ◽  
Koen H. G. Verschueren ◽  
Ann Dansercoer ◽  
Savvas N. Savvides
Keyword(s):  
Citrate Synthase ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Citrate Lyase ◽  
Homology Module
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