It has been reported that the formation of neutrophil extracellular traps (NETs) is associated with cancer metastasis. The current study aimed to explore the effects of NETs on gastric cancer (GC) ...cell metastasis and uncover their underlying mechanism. NETs were measured in the plasma of patients with GC. Then, GC cells were treated with NETs to assess cell viability, migration, and invasion using cell counting kit 8 and Transwell assay, The liver metastasis and xenograft tumor mouse models were established to assess tumor growth and metastasis. The N4-acetylcytidine (ac4C) modification of SET and MYND domain containing 2 (SMYD2) mediated by NAT10 was evaluated using acetylated RNA immunoprecipitation. The results showed that the level of NETs was increased in the plasma of patients with GC, particularly in those with metastatic GC. In addition, GC cell co-treatment with NETs promoted cell viability, migration and invasion, while NAT10 or SMYD2 knockdown abrogated this effect. NAT10 also promoted the ac4C modification of SMYD2, thus increasing SMYD2 stability. Furthermore, NETs promoted the metastasis of GC cells in the liver in vivo. Overall, the results of the present study demonstrated that NETs promoted GC cell metastasis via the NAT10-mediated ac4C modification of SMYD2. These findings suggested that inhibiting the formation of NETs could be an effective approach for attenuating GC progression.
•Neutrophil extracellular traps promote gastric cancer cell migration and invasion.•Neutrophil extracellular traps accelerate tumor growth and liver metastasis.•Neutrophil extracellular traps upregulate the expression of NAT10.•NAT10 promotes the N4-acetylcytidine (ac4C) modification of SMYD2.
As a treasure trove of natural products (NPs), various fungal species possess great potential as cell factories for valuable NPs bioproduction. However, they have many silent biosynthetic gene ...clusters (BGCs), and activation of BGCs expression is critical to the discovery of their indetectable NPs, especially secondary metabolites, in which epigenetic regulation plays a significant role. Thanks to the development of sequencing technologies, more and more epigenetic regulators have been characterized and adopted for boosting fungal NPs production. In this review, at first we summarize various kinds of epigenetic regulation and relevant strategies for triggering fungal NPs biosynthesis. Then, we discuss the limitations of the current strategies, and propose future trends in the discovery of fungi derived NPs by manipulating epigenetics.
•Epigenetic regulation plays a significant role in discovery of the undetectable natural products from fungal species.•Manipulating histone-modifying proteins is a novel manner to activate the expression of biosynthetic gene clusters.•This work provides a systematical view on triggering fungal natural products biosynthesis by epigenetic regulation.
Bone‐derived mesenchymal stem cells (MSCs) reside in a hypoxic niche that maintains their differentiation potential. While hypoxia (low oxygen concentration) was reported to critically support stem ...cell function and osteogenesis, the molecular events triggering changes in stem cell fate decisions in response to normoxia (high oxygen concentration) remain elusive. Here, we study the impact of normoxia on mitochondrial–nuclear communication during stem cell differentiation. We show that normoxia‐cultured murine MSCs undergo profound transcriptional alterations which cause irreversible osteogenesis defects. Mechanistically, high oxygen promotes chromatin compaction and histone hypo‐acetylation, particularly on promoters and enhancers of osteogenic genes. Although normoxia induces metabolic rewiring resulting in elevated acetyl‐CoA levels, histone hypo‐acetylation occurs due to the trapping of acetyl‐CoA inside mitochondria owing to decreased citrate carrier (CiC) activity. Restoring the cytosolic acetyl‐CoA pool remodels the chromatin landscape and rescues the osteogenic defects. Collectively, our results demonstrate that the metabolism–chromatin–osteogenesis axis is perturbed upon exposure to high oxygen levels and identifies CiC as a novel, oxygen‐sensitive regulator of the MSC function.
Synopsis
While low oxygen conditions are established to support mesenchymal stem cell (MSC) differentiation, the impact of normoxia on MSCs remains unclear. This work uncovers increased oxygen levels as a regulator of acetyl‐CoA subcellular localization, impairing histone acetylation and osteogenic differentiation.
A shift from 2 to 21% O2 results in irreversible loss of osteogenic differentiation capacity in murine MSCs.
Normoxia is accompanied by histone hypo‐acetylation and global chromatin compaction, particularly on promoters and enhancers of osteogenic genes.
Histone hypo‐acetylation is caused by reduced activity of mitochondrial citrate transporter (CiC) and impaired export of acetyl‐CoA to the cytosol.
Exposure of mesenchymal stem cells to normoxia impairs osteogenic differentiation due to altered acetyl‐CoA localization within the cell.
•Repeated exposure to sevoflurane can lead to decreased hippocampal neurogenesis and cognitive dysfunction in young mice.•Histone acetylation plays a role in the neurotoxicity of ...sevoflurane.•Restoring histone acetylation can help reverse the inhibition of neurogenesis caused by sevoflurane.
The possibility that exposure to inhalation anaesthetics inhibits neurogenesis and results in memory deficits has attracted considerable interest over the past decade. This study was designed to investigate the mechanism of the sevoflurane exposure-induced decline in hippocampal neurogenesis. Young mice were anaesthetized with a gaseous mixture of 3.0% sevoflurane/60% oxygen 2 h daily for three consecutive days. Sodium butyrate (NaB) administration began 2 h prior to anaesthesia and continued daily until the end of behavioural tests. The Morris water maze (MWM) test was used to determine spatial learning and memory performance. We assessed the effect of repeated sevoflurane exposure on histone acetylation and the expression of brain-derived neurotropic factor (BDNF) and its receptor, tropomyosin-related kinase receptor B (TrkB), in the hippocampus by Western blot (WB). To detect neurogenesis, we first counted the number of neural stem cells (NSCs); we then assessed their proliferation level by immunohistochemistry and estimated the number of new-born cells by immunofluorescence. We found that sevoflurane induced learning and memory deficits in young mice 4 weeks after sevoflurane exposure and that NaB injection restored histone acetylation and improved the performance of the mice in the MWM. NaB also increased the number and proliferation of NSCs and neonatal cells, which were inhibited by sevoflurane. Concomitantly, BDNF and TrkB expression, which was decreased by sevoflurane, was also restored by NaB. Our study showed that sevoflurane affects long-term neurocognitive function and neurogenesis in young mice. Normalization of histone acetylation may alleviate the neurodevelopmental side effects of this anaesthetic.
Hydrogen sulfide (H2S), a gaseous molecule, is involved in modulating multiple physiological functions, such as antioxidant, antihypertension, and the production of polysulfide cysteine. H2S may ...inhibit reactive oxygen species generation and ATP production through modulating respiratory chain enzyme activities; however, the mechanism of this effect remains unclear. In this study, db/db mice, neonatal rat cardiomyocytes, and H9c2 cells treated with high glucose, oleate, and palmitate were used as animal and cellular models of type 2 diabetes. The mitochondrial respiratory rate, respiratory chain complex activities, and ATP production were decreased in db/db mice compared with those in db/db mice treated with exogenous H2S. Liquid chromatography with tandem mass spectrometry analysis showed that the acetylation level of proteins involved in the mitochondrial respiratory chain were increased in the db/db mice hearts compared with those with sodium hydrosulfide (NaHS) treatment. Exogenous H2S restored the ratio of NAD+/NADH, enhanced the expression and activity of sirtuin 3 (SIRT3) and decreased mitochondrial acetylation level in cardiomyocytes under hyperglycemia and hyperlipidemia. As a result of SIRT3 activation, acetylation of the respiratory complexe enzymes NADH dehydrogenase 1 (ND1), ubiquinol cytochrome c reductase core protein 1, and ATP synthase mitochondrial F1 complex assembly factor 1 was reduced, which enhanced the activities of the mitochondrial respiratory chain activity and ATP production. We conclude that exogenous H2S plays a critical role in improving cardiac mitochondrial function in diabetes by upregulating SIRT3.
The diet–microbiota–metabolism relationships during pregnancy are mostly unknown. We explored the effect of the habitual diet and adherence to the dietary reference values on gut microbiota ...composition and diversity. Further, the association of gut microbiota with serum lipidomics and low-grade inflammation was evaluated. Overweight and obese women (BMI 30·7 (sd 4·4) kg/m2, n 100) were studied at early pregnancy (≤17 weeks). Intakes of nutrients were calculated from 3-d food diaries. Faecal microbiota composition was analysed using 16S rRNA gene sequencing. Fasting serum lipidomic profiles were determined by NMR. High-sensitivity C-reactive protein, glycoprotein acetylation (GlycA) and lipopolysaccharide activity were used as markers for low-grade inflammation. The recommended dietary intake of fibre and fat was related to higher gut microbiota richness and lower abundance of Bacteroidaceae. Correlations were observed between gut microbiota richness and GlycA and between a few microbiota genera and serum lipoprotein particles. As a conclusion, adherence to the dietary reference intake of fat and fibre was associated with beneficial gut microbiota composition, which again contributed to lipidomic profile. Higher gut microbiota richness and nutrient intakes were linked to a lower level of low-grade inflammation marker GlycA. This finding offers novel insights and opportunities for dietary modification during pregnancy with potential of improving the health of the mother and the child.
N-terminal acetylation occurs on over 80% of human proteins and is catalyzed by a family of N-terminal acetyltransferases (NATs). All NATs contain a small catalytic subunit, while some also contain a ...large auxiliary subunit that facilitates catalysis and ribosome targeting for co-translational acetylation. NatC is one of the major NATs containing an NAA30 catalytic subunit, but uniquely contains two auxiliary subunits, large NAA35 and small NAA38. Here, we report the cryo-EM structures of human NatC (hNatC) complexes with and without NAA38, together with biochemical studies, to reveal that NAA38 increases the thermostability and broadens the substrate-specificity profile of NatC by ordering an N-terminal segment of NAA35 and reorienting an NAA30 N-terminal peptide binding loop for optimal catalysis, respectively. We also note important differences in engagement with a stabilizing inositol hexaphosphate molecule between human and yeast NatC. These studies provide new insights for the function and evolution of the NatC complex.
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•NAA38 broadens the substrate-specificity profile of NatC•NAA38 reorients an NAA30 N-terminal peptide binding loop for optimal catalysis•NAA38 orders an N-terminal segment of NAA35 and increases NatC thermostability•Unlike in yeast, Inositol hexaphosphate (IP6) does not contribute to NatC stability
The N-terminal acetyltransferases NatC uniquely requires a third small NAA38 subunit for activity. Deng et al. find that NAA38 increases the thermostability and broadens the substrate-specificity profile of NatC by ordering an N-terminal segment of NAA35 and reorienting an NAA30 N-terminal peptide binding loop for optimal catalysis, respectively.
This study was designed to probe the effect of downhill running on microtubule acetylation and autophagic flux in rat skeletal muscle.
Sprague-Dawley rats were subjected to an exercise protocol of a ...90-min downhill run with a slope of -16° and a speed of 16 m·min-1, and then the soleus was sampled at 0, 12, 24, 48, and 72 h after exercise. Protein expression levels of microtubule-associated protein 1 light chain 3 (LC3), p62/sequestosome 1 (p62), α-tubulin, and acetylated α-tubulin (AcK40 α-tubulin) were detected by Western blotting. Alpha-tubulin was costained with AcK40 α-tubulin or cytoplasmic dynein intermediate chain in a single muscle fiber, and LC3 was costained with lysosomal-associated membrane protein 1 in cryosections. To assess autophagic flux in vivo, colchicine or vehicle was injected intraperitoneally 3 d before the exercise experiment, and the protein levels of LC3 and p62 were measured by Western blotting.
Downhill running induced a significant increase in the protein levels of LC3-II and p62, whereas the level and proportion of AcK40 α-tubulin were markedly decreased. Furthermore, the amount of dynein on α-tubulin was decreased after downhill running, and autophagosomes accumulated in the middle of myofibrils. Importantly, LC3-II flux was decreased after downhill running compared with that in the control group.
A bout of downhill running decreases microtubule acetylation, which may impair dynein recruitment and autophagosome transportation, causing blocked autophagic flux.
HIF-1 is closely involved in various biological processes, including angiogenesis, energy metabolism, and cell survival. HIF-1 consists of an oxygen-sensitive HIF-1α and oxygen-insensitive HIF-1β. ...Oxygen-sensitive HIF-1α is subjected to post-translational modifications such as hydroxylation, ubiquitination, and acetylation, which are related to the regulation of its stability. In this present study, we found that the ectopic expression of SUMO-1 increased HIF-1α stability by the co-transfection study with HIF-1α and SUMO-1. Furthermore, the ectopic expression of SUMO-1 enhanced the transcriptional activity of HIF-1α. In the subsequent immunoprecipitation assay, SUMO-1 was co-immunoprecipitated with HIF-1α, implying that HIF-1α is covalently modified by SUMO-1. Thereafter, using a series of lysine mutants in the ODD domain, we found that HIF-1α was sumoylated at Lys
391 and Lys
477, suggesting that sumoylation at these two lysine residues enhances HIF-1α stability by possibly modulating other post-translational modifications. Altogether, we demonstrate that HIF-1α is upregulated through SUMO-1 modification at Lys
391/Lys
477 residues, which may stabilize HIF-1α and enhance its transcriptional activity.
Histone Deacetylases Parbin, Sabnam; Kar, Swayamsiddha; Shilpi, Arunima ...
The journal of histochemistry and cytochemistry,
01/2014, Letnik:
62, Številka:
1
Journal Article
Recenzirano
Odprti dostop
In the current era of genomic medicine, diseases are identified as manifestations of anomalous patterns of gene expression. Cancer is the principal example among such maladies. Although remarkable ...progress has been achieved in the understanding of the molecular mechanisms involved in the genesis and progression of cancer, its epigenetic regulation, particularly histone deacetylation, demands further studies. Histone deacetylases (HDACs) are one of the key players in the gene expression regulation network in cancer because of their repressive role on tumor suppressor genes. Higher expression and function of deacetylases disrupt the finely tuned acetylation homeostasis in both histone and non-histone target proteins. This brings about alterations in the genes implicated in the regulation of cell proliferation, differentiation, apoptosis and other cellular processes. Moreover, the reversible nature of epigenetic modulation by HDACs makes them attractive targets for cancer remedy. This review summarizes the current knowledge of HDACs in tumorigenesis and tumor progression as well as their contribution to the hallmarks of cancer. The present report also describes briefly various assays to detect histone deacetylase activity and discusses the potential role of histone deacetylase inhibitors as emerging epigenetic drugs to cure cancer.
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