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Acetyl-CoA promotes cell adhesion and migration in GBM cells. (A) Relative mRNA levels of acetyl-CoA-up-regulated genes as determined by RT-qPCR in LN229 cells. (#) P < 0.05; (##) P < 0.01, significance of acetate treated over 1 mM glucose. ( * * ) P < 0.01; ( * * * ) P < 0.001, significance of 10 mM glucose treated over 1 mM glucose. (B) Wound healing assay in LN229 cells. ( * * * ) P < 0.001; ( * * * * ) P < 0.0001. (Right panel) Lines indicate the boundary of the scratch. Photos were captured at 0 h and after 24 h. (C) Transwell migration of LN229 across an 8.0-µm polycarbonate membrane. ( * ) P < 0.05; ( * * ) P < 0.01. (Right panel) Cells on the membrane were stained with Hoechst, and photos were captured 24 h after seeding. (D) Adhesion quantified on biomaterial platform with ECM components of the brain. Cells were pretreated with the indicated conditions for 24 h, and the area covered by cells was measured over time. ( * ) P < 0.05, significance of acetate conditions over 1 mM glucose conditions determined by Tukey's post hoc test. (E-H) Relative adhesion to 1% fibronectin after 24 h of the indicated treatments in LN229 (E), LN18 (F ), U87 (G), and U251 (H) cells. ( * * ) P < 0.01; ( * * * ) P < 0.001; ( * * * * ) P < 0.0001. (I ) LN229 cells were incubated in 1 mM glucose overnight, and then the medium was changed to the indicated conditions. Quantification of adhesion to 1% fibronectin after the indicated hours of treatment. ( * * ) P < 0.01; ( * * * ) P < 0.001; ( * * * * ) P < 0.0001. All panels show mean ± SEM of triplicates.
Source publication
The metabolite acetyl-coenzyme A (acetyl-CoA) is the required acetyl donor for lysine acetylation and thereby links metabolism, signaling, and epigenetics. Nutrient availability alters acetyl-CoA levels in cancer cells, correlating with changes in global histone acetylation and gene expression. However, the specific molecular mechanisms through whi...
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... interactions; and KEGG: ECM-receptor interac- tion) ( Lee et al. 2014). To confirm these findings, mRNA expression patterns for select genes within these sets were validated by RT-qPCR in LN229 GBM cells, compar- ing low-glucose (1 mM glucose), high-glucose (10 mM glu- cose), and low-glucose plus acetate (1 mM glucose + 5 mM acetate) conditions (Fig. 1A). Given this regulation of cell adhesion and migration genes by glucose and acetate, we next investigated whether acetyl-CoA abundance impacts the ability of cells to migrate using wound healing and transwell migration assays. In both assays, cell migration was impaired in low-glucose conditions and rescued by ac- etate supplementation ...
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... (Fig. 1A). Given this regulation of cell adhesion and migration genes by glucose and acetate, we next investigated whether acetyl-CoA abundance impacts the ability of cells to migrate using wound healing and transwell migration assays. In both assays, cell migration was impaired in low-glucose conditions and rescued by ac- etate supplementation (Fig. ...
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... comprised of 50% fibronectin, 25% vitronectin, 20% tenascin C, and 5% laminin ( Barney et al. 2015). After incubating cells in high or low glucose with or without acetate supplementation, cells were seed- ed onto the ECM, and their adhesion kinetics were quanti- fied. Both glucose and acetate enhanced LN229 cell adhesion to the brain-inspired ECM (Fig. 1D) as well as to fibronectin alone (Fig. 1E). Similar observations were also made with three other GBM cell lines (Fig. 1F-H). Im- portantly, acetate rescued adhesion and migration without impacting cell doubling time ( Lee et al. 2014), AMPK acti- vation (Supplemental Fig. S1A), or markers of the unfolded protein response (Supplemental ...
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... 20% tenascin C, and 5% laminin ( Barney et al. 2015). After incubating cells in high or low glucose with or without acetate supplementation, cells were seed- ed onto the ECM, and their adhesion kinetics were quanti- fied. Both glucose and acetate enhanced LN229 cell adhesion to the brain-inspired ECM (Fig. 1D) as well as to fibronectin alone (Fig. 1E). Similar observations were also made with three other GBM cell lines (Fig. 1F-H). Im- portantly, acetate rescued adhesion and migration without impacting cell doubling time ( Lee et al. 2014), AMPK acti- vation (Supplemental Fig. S1A), or markers of the unfolded protein response (Supplemental Fig. S1B), suggesting that the adhesion ...
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... in high or low glucose with or without acetate supplementation, cells were seed- ed onto the ECM, and their adhesion kinetics were quanti- fied. Both glucose and acetate enhanced LN229 cell adhesion to the brain-inspired ECM (Fig. 1D) as well as to fibronectin alone (Fig. 1E). Similar observations were also made with three other GBM cell lines (Fig. 1F-H). Im- portantly, acetate rescued adhesion and migration without impacting cell doubling time ( Lee et al. 2014), AMPK acti- vation (Supplemental Fig. S1A), or markers of the unfolded protein response (Supplemental Fig. S1B), suggesting that the adhesion and migration phenotypes are not secondary to effects on proliferation, ...
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... and acetate enhanced LN229 cell adhesion to the brain-inspired ECM (Fig. 1D) as well as to fibronectin alone (Fig. 1E). Similar observations were also made with three other GBM cell lines (Fig. 1F-H). Im- portantly, acetate rescued adhesion and migration without impacting cell doubling time ( Lee et al. 2014), AMPK acti- vation (Supplemental Fig. S1A), or markers of the unfolded protein response (Supplemental Fig. S1B), suggesting that the adhesion and migration phenotypes are not secondary to effects on proliferation, bioenergetics, or endoplasmic reticulum (ER) stress. On the other hand, acetate restored histone acetylation levels in low-glucose conditions, and inhibition of the ...
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... (Fig. 1D) as well as to fibronectin alone (Fig. 1E). Similar observations were also made with three other GBM cell lines (Fig. 1F-H). Im- portantly, acetate rescued adhesion and migration without impacting cell doubling time ( Lee et al. 2014), AMPK acti- vation (Supplemental Fig. S1A), or markers of the unfolded protein response (Supplemental Fig. S1B), suggesting that the adhesion and migration phenotypes are not secondary to effects on proliferation, bioenergetics, or endoplasmic reticulum (ER) stress. On the other hand, acetate restored histone acetylation levels in low-glucose conditions, and inhibition of the lysine acetyltransferase (KAT) p300 sup- pressed glucose-and ...
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... to effects on proliferation, bioenergetics, or endoplasmic reticulum (ER) stress. On the other hand, acetate restored histone acetylation levels in low-glucose conditions, and inhibition of the lysine acetyltransferase (KAT) p300 sup- pressed glucose-and acetate-dependent increases in global H3K27ac and cell adhesion to the ECM (Supplemental Fig. S1C,D), consistent with a potential role for histone acety- lation in promoting these phenotypes. These data suggest that acetyl-CoA promotes GBM cell adhesion to ECM in a p300-dependent ...
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... the time required for cells to adhere following glucose and ac- etate supplementation. Cells were incubated overnight in 1 mM glucose, then glucose or acetate was added, and ad- hesion was subsequently measured over 24 h. Increased fi- bronectin adhesion was observed beginning 4 h after glucose or acetate addition and further increased after 24 h (Fig. 1I). These data are consistent with a mechanism whereby gene transcription rather than a more acute sig- naling mechanism mediates glucose-and acetate-induced cell adhesion to the ECM. ( * * ) P < 0.01; ( * * * ) P < 0.001; ( * * * * ) P < 0.0001. (I ) LN229 cells were incubated in 1 mM glucose overnight, and then the medium was changed ...
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... availability. To investigate this, we performed H3K27ac chromatin immunoprecipitation (ChIP) coupled with next-generation sequencing (ChIP-seq). We focused on H3K27ac, since it has important roles in gene regula- tion and is mediated by CBP/p300 ( Feller et al. 2015), which is also required for glucose-and acetate-dependent adhesion (Supplemental Fig. S1D). The overall distribu- tion of H3K27ac peaks throughout the genome was similar between conditions (Supplemental Fig. S3A). Since tradi- tional ChIP-seq data normalization to percentage of reads fails to account for differences in the abundance of histone modification between conditions, we used an exogenous reference genome ...
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... the ratio of total H3K27ac reads align- ing to the Homo sapiens genome versus the D. mela- nogaster genome decreased markedly in low glucose and increased with acetate supplementation (Supplemental Fig. S3B). These data are consistent with the pronounced changes in global H3K27ac observed in these conditions by Western blot (Supplemental Fig. S1C). We next aimed to broadly evaluate the genome-wide loci at which H3K27ac was gained in high-glucose or acetate-supple- mented conditions compared with the 1 mM glucose con- dition. Using a stringent computational tool, DiffBind, we identified 1091 regions that gained peaks. When the near- est genes were analyzed, only a small fraction ...
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... comprises a family of four Ca 2+ -regulated tran- scription factors, which control diverse cellular processes in a wide range of cell types (Mancini and Toker 2009;Muller and Rao 2010). NFAT isoforms also interact with the coactivator p300 (Garcia-Rodriguez and Rao 1998), a KAT that facilitates nutrient-dependent adhesion (Sup- plemental Fig. S1D). Notably, NFAT has a well-estab- lished role in not only regulating migration of normal cells but also tissue invasion by cancer cells (Qin et al. 2014) and has been implicated in the pathogenesis of GBM ( Tie et al. 2013;Wang et al. 2015). However, few NFAT-regulated genes have been identified in gliomas, and NFAT sensitivity to ...
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... availability and the mechanisms through which specific genes are regulated by acetyl- CoA. The marked reduction in H. sapiens versus spiked- in D. melanogaster reads observed by H3K27ac ChIP-Rx under low-glucose conditions (Supplemental Fig. S3B) is consistent with the striking suppression in global H3K27ac seen by Western blot (Supplemental Fig. S1C) as well as with glucose-dependent alterations in multiple histone acetyl marks recorded by mass spectrometry ( Lee et al. 2014). While potent regulation of H3K27ac at the promoter TSSs of acetyl-CoA-up-regulated genes was observed (Fig. 3C,D), these changes occur at a relatively small number of genes and cannot account for the global ...
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Histone lysine acetylation is an essential chromatin modification for epigenetic regulation of gene expression during plant response to stress. On the other hand, enzymes involved in histone acetylation homeostasis require primary metabolites as substrates or cofactors whose levels are greatly influenced by stress and growth conditions in plants. I...
Citations
... Mechanistically, nuclear factor of activated T-cells (NFAT1) has been identified as a key mediator of the acetyl-CoA-dependent regulation of genes related to adhesion and migration. Additionally, high levels of acetyl-CoA regulate NFAT1 by controlling Ca 2+ homeostasis, leading to NFAT1 dephosphorylation and its nuclear translocation [30]. GBMs primarily rely on acetate as a source of acetyl-CoA. ...
... Cell migration and adhesion [30] Tumor proliferation [31] α-KG Tumor survival [68] Pyruvate DNA repair [74] Colorectal cancer (CRC) SAM Metastasis [44] Lymphoma Succinate Tumorigenesis [53] Leukemia R-2HG Tumorigenesis, anti-proliferation [34,35,55] Lung cancer UDP-glucose, UDP-glucuronic acid Metastasis [58] Citrate Anti-proliferation [64] α-KG Metastasis [67] Succinate TAM polarization and cancer metastasis [62] Prostate cancer Succinate TAM polarization and cancer metastasis [62] Neuroendocrine prostate cancer (NEPC) Serine, SAM Tumor proliferation [48] mTORC1-driven tumor (melanoma, prostate cancer, lung cancer.) ...
Metabolic reprogramming has emerged as a prominent hallmark of cancer, characterized by substantial alterations in nutrient uptake and intracellular metabolic pathways. Consequently, intracellular metabolite concentrations undergo significant changes which can contribute to tumorigenesis through diverse mechanisms. Beyond their classical roles in regulating metabolic pathway flux, metabolites exhibit noncanonical functions that play a crucial role in tumor progression. In this review, we delve into the nonclassical functions of metabolites in the context of tumor progression, with a particular focus on their capacity to modulate gene expression and cell signaling. Furthermore, we discuss the potential exploitation of these nonclassical functions in the enhancement of cancer therapy.
... 48 Moreover, ACLY plays a role in facilitating the migration and adhesion of glioblastoma cells to the extracellular matrix (ECM) via nuclear factor of activated T cells (NFAT1). 49 Specifically, the production of acetyl-CoA dependent on ACLY stimulates the dephosphorylation and nuclear translocation of NFAT1 by modulating Ca2 + signals. Thus, NFAT family transcription factors drive the expression of cell adhesion genes and implement the biological function of promoting tumor cell migration. ...
... Thus, NFAT family transcription factors drive the expression of cell adhesion genes and implement the biological function of promoting tumor cell migration. 49 ACC is the rate-limiting enzyme in fatty acid synthesis, emerging as a notable determinant impacting acetyl-CoA levels and lipogenesis in cancer. 50 Transforming growth factor β (TGF-β) and leptin were shown to induce ACC1 phosphorylation and inactivation in breast cancer mediated by TGFβ-activated kinase, contributing to the elevation of cellular acetyl-CoA. ...
Epigenetic modifications are defined as heritable changes in gene activity that do not involve changes in the underlying DNA sequence. The oncogenic process is driven by the accumulation of alterations that impact genome's structure and function. Genetic mutations, which directly disrupt the DNA sequence, are complemented by epigenetic modifications that modulate gene expression, thereby facilitating the acquisition of malignant characteristics. Principals among these epigenetic changes are shifts in DNA methylation and histone mark patterns, which promote tumor development and metastasis. Notably, the reversible nature of epigenetic alterations, as opposed to the permanence of genetic changes, positions the epigenetic machinery as a prime target in the discovery of novel therapeutics. Our review delves into the complexities of epigenetic regulation, exploring its profound effects on tumor initiation, metastatic behavior, metabolic pathways, and the tumor microenvironment. We place a particular emphasis on the dysregulation at each level of epigenetic modulation, including but not limited to, the aberrations in enzymes responsible for DNA methylation and histone modification, subunit loss or fusions in chromatin remodeling complexes, and the disturbances in higher‐order chromatin structure. Finally, we also evaluate therapeutic approaches that leverage the growing understanding of chromatin dysregulation, offering new avenues for cancer treatment.
... 98 Increased levels of acetyl-CoA have also been observed in other cancer types, including breast cancer, glioblastoma, and prostate cancer, indicative of the pro-metastatic role of this metabolite. [100][101][102] Thus, anaplerosis and cataplerosis provide survival flexibility to HCC in the hostile environment of a tumor. ...
Hepatocellular carcinoma (HCC) is the primary form of liver cancer. It causes ∼ 800 000 deaths per year, which is expected to increase due to increasing rates of obesity and metabolic dysfunction associated steatotic liver disease (MASLD). Current therapies include immune checkpoint inhibitors, tyrosine kinase inhibitors, and monoclonal antibodies, but these therapies are not satisfactorily effective and often come with multiple side effects and recurrences. Metabolic reprogramming plays a significant role in HCC progression and is often conserved between tumor types. Thus, targeting rewired metabolic pathways could provide an attractive option for targeting tumor cells alone or in conjunction with existing treatments. Therefore, there is an urgent need to identify novel targets involved in cancer-mediated metabolic reprogramming in HCC. In this review, we provide an overview of molecular rewiring and metabolic reprogramming of glucose metabolism in HCC to understand better the concepts that might widen the therapeutic window against this deadly cancer.
... 10,11 For example, fluctuations in acetyl-CoA affect histone acetylation levels, which influence transcription of oncogenes in GBM. 12 With a better understanding of this regulatory model, we might modulate essential genes more precisely, thus providing new insights into treatment of glioma. ...
... 35 Indeed, intracellular acetyl-CoA abundance enhanced the global levels of histone acetylation and the expression of various genes linked to cell adhesion and migration. 12,35 Moreover, acetyl-CoA-mediated nuclear factor of activated T-cells (NFAT1) activation has been shown to contribute to site-specific modulation of histone acetylation, such as H3K27ac. 12 In LN229 and GBM#P3 cells, we found that nuclear accumulation of NFAT1 was inhibited after knockdown of HMGCL ( Figure 3D and Figure S4A and B). ...
... 12,35 Moreover, acetyl-CoA-mediated nuclear factor of activated T-cells (NFAT1) activation has been shown to contribute to site-specific modulation of histone acetylation, such as H3K27ac. 12 In LN229 and GBM#P3 cells, we found that nuclear accumulation of NFAT1 was inhibited after knockdown of HMGCL ( Figure 3D and Figure S4A and B). Both glucose and acetate have been shown to serve as substrates for acetyl-CoA production. ...
Background
Altered branched-chain amino acid (BCAA) metabolism modulates epigenetic modification, such as H3K27ac in cancer, thus providing a link between metabolic reprogramming and epigenetic change, which are prominent hallmarks of glioblastoma multiforme (GBM). Here, we identified mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase (HMGCL), an enzyme involved in leucine degradation, promoting GBM progression and glioma stem cell (GSC) maintenance.
Methods
In silico analysis was performed to identify specific molecules involved in multiple processes. Glioblastoma multiforme cells were infected with knockdown/overexpression lentiviral constructs of HMGCL to assess malignant performance in vitro and in an orthotopic xenograft model. RNA sequencing was used to identify potential downstream molecular targets.
Results
HMGCL, as a gene, increased in GBM and was associated with poor survival in patients. Knockdown of HMGCL suppressed proliferation and invasion in vitro and in vivo. Acetyl-CoA was decreased with HMGCL knockdown, which led to reduced NFAT1 nuclear accumulation and H3K27ac level. RNA sequencing-based transcriptomic profiling revealed FOXM1 as a candidate downstream target, and HMGCL-mediated H3K27ac modification in the FOXM1 promoter induced transcription of the gene. Loss of FOXM1 protein with HMGCL knockdown led to decreased nuclear translocation and thus activity of β-catenin, a known oncogene. Finally, JIB-04, a small molecule confirmed to bind to HMGCL, suppressed GBM tumorigenesis in vitro and in vivo.
Conclusions
Changes in acetyl-CoA levels induced by HMGCL altered H3K27ac modification, which triggers transcription of FOXM1 and β-catenin nuclear translocation. Targeting HMGCL by JIB-04 inhibited tumor growth, indicating that mediators of BCAA metabolism may serve as molecular targets for effective GBM treatment.
... Similarly, 2-deoxy-d-glucose treatment mimicked glucose starvation to reduce histone acetylation in a dose-dependent manner (Cluntun et al. 2015). Moreover, in glioblastoma cells, glucose withdrawal compromised the expression of several important genes involved in cell migration and adhesion to the extracellular matrix, presumably due to the coordinated depletion of site-specific histone H3 lysine 27 acetylation (H3K27ac) and defective acetylation-dependent nuclear translocation of the transcription factor NFAT1 (Lee et al. 2018). These results demonstrate a critical role for glucose-dependent gene expression and suggest that cancer cells growing in glucose-limited conditions may face evolutionary pressures to acquire acetyl-CoA from alternative sources such as acetate or glutamine. ...
A century ago, Otto Heinrich Warburg made a seminal discovery now known as the Warburg effect. This metabolic signature, prevalent across all cancer cells, is characterized by the prominent shift of glucose metabolism toward lactate production instead of oxidative respiration. Warburg's pioneering theory suggested that the induction of the Warburg effect instigates dedifferentiation and the process of tumorigenesis, illuminating a fundamental mechanism underlying cancer development. To celebrate the centennial anniversary of Warburg's monumental finding, it is an appropriate moment to reflect upon and commemorate his revolutionary contributions to the fields of metabolism and cancer research. In this review, we explore the role of mitochondria in epigenetic regulation and the decisions governing cell fate from an evolutionary standpoint. Moreover, we summarize metabolic and genetic factors that trigger the Warburg effect, underscoring the therapeutic potential of mitochondrial uncoupling as a strategy to counter this metabolic aberration. Our goal is to elucidate the means to induce tumor differentiation through metabolic therapy, thereby laying a foundation toward the cure for cancer.
Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... Blood coagulation cascade, immune system process [35,36] CBR1 PGE2 is converted to PGF2a by CBR1 CBR1 inactivates highly reactive lipid aldehydes and may play a meaningful role in preserving cells from oxidative stress. Inhibition of CBR1 induces accumulation of intracellular ROS levels leading to an increase in mitotic catastrophe and mitotic arrest. ...
... Meanwhile, among the 33 independent and significant genes, CHST2, PPCS, and FBXO17 were considered to influence the prognosis of GBM in relation to metabolism [23,29,35,36]. The role of CHST2 in GBM is largely unknown, however, it is thought to have a negative influence on long-term survival in GBM patients in our study. ...
Background and purpose
Glioblastoma multiforme (GBM) is the most devastating brain tumor with less than 5% of patients surviving 5 years following diagnosis. Many studies have focused on the genetics of GBM with the aim of improving the prognosis of GBM patients. We investigated specific genes whose expressions are significantly related to both the length of the overall survival and the progression-free survival in patients with GBM.
Methods
We obtained data for 12,042 gene mRNA expressions in 525 GBM tissues from the Cancer Genome Atlas (TCGA) database. Among those genes, we identified independent genes significantly associated with the prognosis of GBM. Receiver operating characteristic (ROC) curve analysis was performed to determine the genes significant for predicting the long-term survival of patients with GBM. Bioinformatics analysis was also performed for the significant genes.
Results
We identified 33 independent genes whose expressions were significantly associated with the prognosis of 525 patients with GBM. Among them, the expressions of five genes were independently associated with an improved prognosis of GBM, and the expressions of 28 genes were independently related to a poorer prognosis of GBM. The expressions of the ADAM22 , ATP5C1 , RAC3 , SHANK1 , AEBP1 , C1RL , CHL1 , CHST2 , EFEMP2 , and PGCP genes were either positively or negatively related to the long-term survival of GBM patients.
Conclusions
Using a large-scale and open database, we found genes significantly associated with both the prognosis and long-term survival of patients with GBM. We believe that our findings may contribute to improving the understanding of the mechanisms underlying GBM.
... Earlier studies indicated that NFAT could regulate the recruitment of effector cells to inflammatory sites to participate in host defense by regulating the transcription of chemokines and inflammatory factors [66][67][68] . In addition, many studies have indicated that NFAT has a well-established role in promoting cell adhesion and migration [69][70][71] , which is consistent with a mechanism in which adhesion-dependent trogocytosis is regulated by NFAT. Interestingly, Pontrelli and colleagues reported that cyclosporine A (another inhibitor of NFAT signaling) could inhibit cytoskeletal reorganization 71 , which is a key requirement for amebic trogocytosis 49 . ...
Schistosoma parasites, causing schistosomiasis, exhibit typical host specificity in host preference. Many mammals, including humans, are susceptible to infection, while the widely distributed rodent, Microtus fortis, exhibits natural anti-schistosome characteristics. The mechanisms of host susceptibility remain poorly understood. Comparison of schistosome infection in M. fortis with the infection in laboratory mice (highly sensitive to infection) offers a good model system to investigate these mechanisms and to gain an insight into host specificity. In this study, we showed that large numbers of leukocytes attach to the surface of human schistosomes in M. fortis but not in mice. Single-cell RNA-sequencing analyses revealed that macrophages might be involved in the cell adhesion, and we further demonstrated that M. fortis macrophages could be mediated to attach and kill schistosomula with dependence on Complement component 3 (C3) and Complement receptor 3 (CR3). Importantly, we provided direct evidence that M. fortis macrophages could destroy schistosomula by trogocytosis, a previously undescribed mode for killing helminths. This process was regulated by Ca2+/NFAT signaling. These findings not only elucidate a novel anti-schistosome mechanism in M. fortis but also provide a better understanding of host parasite interactions, host specificity and the potential generation of novel strategies for schistosomiasis control.
... Histone Hypoacetylation to Restore ERα Expression. In addition to the known correlation between acetyl-CoA levels with histone acetylation (34,35), previous studies had demonstrated that under conditions limiting glucose (36,37) or oxygen availability (38,39), cells engage alternate sources of acetyl-CoA such as acetate to maintain histone acetylation. This metabolic switch is thought to be mediated by either ACSS2 activity or through the ACSS1/3 to ACLY pathway (Fig. 3E) (40)(41)(42). ...
Loss of estrogen receptor (ER) pathway activity promotes breast cancer progression, yet how this occurs remains poorly understood. Here, we show that serine starvation, a metabolic stress often found in breast cancer, represses estrogen receptor alpha (ERα) signaling by reprogramming glucose metabolism and epigenetics. Using isotope tracing and time-resolved metabolomic analyses, we demonstrate that serine is required to maintain glucose flux through glycolysis and the TCA cycle to support acetyl-CoA generation for histone acetylation. Consequently, limiting serine depletes histone H3 lysine 27 acetylation (H3K27ac), particularly at the promoter region of ER pathway genes including the gene encoding ERα, ESR1 . Mechanistically, serine starvation impairs acetyl-CoA-dependent gene expression by inhibiting the entry of glycolytic carbon into the TCA cycle and down-regulating the mitochondrial citrate exporter SLC25A1, a critical enzyme in the production of nucleocytosolic acetyl-CoA from glucose. Consistent with this model, total H3K27ac and ERα expression are suppressed by SLC25A1 inhibition and restored by acetate, an alternate source of acetyl-CoA, in serine-free conditions. We thus uncover an unexpected role for serine in sustaining ER signaling through the regulation of acetyl-CoA metabolism.
... Under the pathological state, acetyl-CoA play important roles in tumor migration. For example, in glioblastoma, it promotes the expression of cell migration and adhesion-related genes by controlling Ca 2+ and nuclear factor of activated T called signaling [72,80]. In pancreatic carcinogenesis, histone acetylation facilitates cell plasticity and proliferation [81]. ...
Mitochondria are intracellular organelles involved in energy production, cell metabolism and cell signaling. They are essential not only in the process of ATP synthesis, lipid metabolism and nucleic acid metabolism, but also in tumor development and metastasis. Mutations in mtDNA are commonly found in cancer cells to promote the rewiring of bioenergetics and biosynthesis, various metabolites especially oncometabolites in mitochondria regulate tumor metabolism and progression. And mutation of enzymes in the TCA cycle leads to the unusual accumulation of certain metabolites and oncometabolites. Mitochondria have been demonstrated as the target for cancer treatment. Cancer cells rely on two main energy resources: oxidative phosphorylation (OXPHOS) and glycolysis. By manipulating OXPHOS genes or adjusting the metabolites production in mitochondria, tumor growth can be restrained. For example, enhanced complex I activity increases NAD + /NADH to prevent metastasis and progression of cancers. In this review, we discussed mitochondrial function in cancer cell metabolism and specially explored the unique role of mitochondria in cancer stem cells and the tumor microenvironment. Targeting the OXPHOS pathway and mitochondria-related metabolism emerging as a potential therapeutic strategy for various cancers.
... Fatty acid synthesis (FAS), unlike oxidation, occurs in the cytoplasm, in which citrate acts as a substrate for ATP-citrate lyase (which has been previously targeted using several inhibitors; refs. [27][28][29] to produce cytosolic acetyl-CoA (13). This occurs in the cytoplasm due to the availability of NADPH, which is a required cofactor for FA biosynthetic reactions. ...
Glioblastoma (GBM) is a primary tumor of the brain defined by its uniform lethality and resistance to conventional therapies. There have been considerable efforts to untangle the metabolic underpinnings of this disease to find novel therapeutic avenues for treatment. An emerging focus in this field is fatty acid (FA) metabolism, which is critical for numerous diverse biological processes involved in GBM pathogenesis. These processes can be classified into four broad fates: anabolism, catabolism, regulation of ferroptosis, and the generation of signaling molecules. Each fate provides a unique perspective by which we can inspect GBM biology and gives us a road map to understanding this complicated field. This Review discusses the basic, translational, and clinical insights into each of these fates to provide a contemporary understanding of FA biology in GBM. It is clear, based on the literature, that there are far more questions than answers in the field of FA metabolism in GBM, and substantial efforts should be made to untangle these complex processes in this intractable disease.
