bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2022‒06‒12
nine papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Cancers (Basel). 2022 May 27. pii: 2655. [Epub ahead of print]14(11):
      Metabolic alterations in neoplastic cells have recently gained increasing attention as a main topic of research, playing a crucial regulatory role in the development and progression of tumors. The interplay between epigenetic modifications and metabolic pathways in glioblastoma cells has emerged as a key pathogenic area with great potential for targeted therapy. Epigenetic mechanisms have been demonstrated to affect main metabolic pathways, such as glycolysis, pentose phosphate pathway, gluconeogenesis, oxidative phosphorylation, TCA cycle, lipid, and glutamine metabolism by modifying key regulatory genes. Although epigenetic modifications can primarily promote the activity of metabolic pathways, they may also exert an inhibitory role. In this way, they participate in a complex network of interactions that regulate the metabolic behavior of malignant cells, increasing their heterogeneity and plasticity. Herein, we discuss the main epigenetic mechanisms that regulate the metabolic pathways in glioblastoma cells and highlight their targeting potential against tumor progression.
    Keywords:  DNA; Krebs cycle; TCA cycle; acetylation; glioblastoma; glioma; gluconeogenesis; glutamine; glycolysis; histones; methylation; microRNAs; oxidative phosphorylation; pentose phosphate pathway
  2. Nat Cell Biol. 2022 Jun 06.
      Mitochondrial metabolites regulate leukaemic and normal stem cells by affecting epigenetic marks. How mitochondrial enzymes localize to the nucleus to control stem cell function is less understood. We discovered that the mitochondrial metabolic enzyme hexokinase 2 (HK2) localizes to the nucleus in leukaemic and normal haematopoietic stem cells. Overexpression of nuclear HK2 increases leukaemic stem cell properties and decreases differentiation, whereas selective nuclear HK2 knockdown promotes differentiation and decreases stem cell function. Nuclear HK2 localization is phosphorylation-dependent, requires active import and export, and regulates differentiation independently of its enzymatic activity. HK2 interacts with nuclear proteins regulating chromatin openness, increasing chromatin accessibilities at leukaemic stem cell-positive signature and DNA-repair sites. Nuclear HK2 overexpression decreases double-strand breaks and confers chemoresistance, which may contribute to the mechanism by which leukaemic stem cells resist DNA-damaging agents. Thus, we describe a non-canonical mechanism by which mitochondrial enzymes influence stem cell function independently of their metabolic function.
  3. Cancers (Basel). 2022 May 26. pii: 2643. [Epub ahead of print]14(11):
      BACKGROUND: The mechanism of action of romidepsin and other histone deacetylase inhibitors is still not fully explained. Our goal was to gain a mechanistic understanding of the RAS-linked phenotype associated with romidepsin sensitivity.METHODS: The NCI60 dataset was screened for molecular clues to romidepsin sensitivity. Histone acetylation, DNA damage, ROS production, metabolic state (real-time measurement and metabolomics), and gene expression alterations (transcriptomics) were determined in KRAS-WT versus KRAS-mutant cell groups. The search for biomarkers in response to HDACi was implemented by supervised machine learning analysis on a 608-cell transcriptomic dataset and validated in a clinical dataset.
    RESULTS: Romidepsin treatment induced depletion in acetyl-CoA in all tested cell lines, which led to oxidative stress, metabolic stress, and increased death-particularly in KRAS-mutant cell lines. Romidepsin-induced stresses and death were rescued by acetyl-CoA replenishment. Two acetyl-CoA gene expression signatures associated with HDACi sensitivity were derived from machine learning analysis in the CCLE (Cancer Cell Line Encyclopedia) cell panel. Signatures were then validated in the training cohort for seven HDACi, and in an independent 13-patient cohort treated with belinostat.
    CONCLUSIONS: Our study reveals the importance of acetyl-CoA metabolism in HDAC sensitivity, and it highlights acetyl-CoA generation pathways as potential targets to combine with HDACi.
    Keywords:  HDAC inhibitors; RAS; acetyl-CoA metabolism
  4. J Zhejiang Univ Sci B. 2022 Jun 15. pii: 1673-1581(2022)06-0461-20. [Epub ahead of print]23(6): 461-480
      The negative effects of low temperature can readily induce a variety of diseases. We sought to understand the reasons why cold stress induces disease by studying the mechanisms of fine-tuning in macrophages following cold exposure. We found that cold stress triggers increased macrophage activation accompanied by metabolic reprogramming of aerobic glycolysis. The discovery, by genome-wide RNA sequencing, of defective mitochondria in mice macrophages following cold exposure indicated that mitochondrial defects may contribute to this process. In addition, changes in metabolism drive the differentiation of macrophages by affecting histone modifications. Finally, we showed that histone acetylation and lactylation are modulators of macrophage differentiation following cold exposure. Collectively, metabolism-related epigenetic modifications are essential for the differentiation of macrophages in cold-stressed mice, and the regulation of metabolism may be crucial for alleviating the harm induced by cold stress.
    Keywords:  Autophagy; Histone; Low temperature; Metabolic reprogramming; Stress
  5. FEBS Lett. 2022 Jun 03.
      Mitochondria are involved in many cellular activities, including energy metabolism and biosynthesis of nucleotides, fatty acids, and amino acids. Mitochondrial morphology is a key factor in dictating mitochondrial functions. Here, we report that the acyl-CoA binding protein Acb1 in the fission yeast Schizosaccharomyces pombe is required for the maintenance of tubular mitochondrial morphology and proper mitochondrial respiration. The absence of Acb1 causes severe mitochondrial fragmentation in a dynamin-related protein Dnm1-dependent manner and impairs mitochondrial respiration. Moreover, Acb1 regulates the remodeling of lipid droplets in nutrient-rich conditions. Importantly, Acb1 promotes cell survival when cells are cultured in nutrient-rich medium. Hence, our findings establish roles of acyl-CoA binding proteins in regulating mitochondria, lipid droplets, and cell viability.
    Keywords:  Acyl-CoA-Binding Protein; Cell proliferation; Lipid droplets; Mitochondria; Schizosaccharomyces pombe
  6. Adv Nutr. 2022 Jun 09. pii: nmac067. [Epub ahead of print]
      Dietary components can induce epigenetic changes through DNA methylation, histone modification, and regulation of microRNAs (miRNAs). Studies of diet-induced epigenetic regulation can inform anticipatory trials and fine-tune public health guidelines. We systematically reviewed data on the effect of extra virgin olive oil (EVOO) and its phenolic compounds (OOPCs) on the epigenetic landscape. We conducted a literature search using PubMed, Scopus, and Web of Science databases and scrutinized published evidence. After applying selection criteria (e.g., inclusion of in vitro, animal, or human studies supplemented with EVOO or its OOPCs), we thoroughly reviewed 51 articles, and the quality assessment was performed using the revised Cochrane risk of bias tool. The results show that both EVOO and its OOPCs can promote epigenetic changes capable of regulating the expression of genes and molecular targets involved in different metabolic processes. For example, oleuropein (OL) may be an epigenetic regulator in cancer; and hydroxytyrosol (HT) modulates the expression of miRNAs involved in the development of cancer, cardiovascular, and neurodegenerative diseases. We conclude that EVOO and its OPPCs can regulate gene expression by modifying epigenetic mechanisms and impact human pathophysiology. A full elucidation of the epigenetics effects of EVOO and its OOPCs may contribute to developing different pharma-nutritional strategies that exploit them as epigenetic agents.
    Keywords:  DNA methylation; histone modification; hydroxytyrosol; mirna; oleuropein; phenolic compounds
  7. Toxicol Appl Pharmacol. 2022 Jun 06. pii: S0041-008X(22)00244-7. [Epub ahead of print] 116099
      Celastrol, a natural triterpene from the Tripterygium wilfordii has been demonstrated to possess attributive properties to attenuate various animal models of obesity-associated conditions. The present study aimed to elucidate the putative targets of celastrol on intracellular glucose utilization and mitochondrial oxidative metabolism in the isolated quadriceps skeletal muscle of high-fat diet (HFD)-induced obese male C57BL6/J mice. Here we showed that celastrol remarkably attenuated obesity and insulin resistance through improvement of systemic glucose tolerance and insulin sensitivity. Enhanced mRNA transcription factors of key rate-limiting glycolytic and TCA cycle enzymes were observed following celastrol administration. The metabolic profiling revealed profound changes induced by celastrol administration on several key metabolites of glycolysis and tricarboxylic acid (TCA) cycle including glucose-1-phosphate, pyruvate, citrate, α-ketoglutarate, succinate and fumarate. Celastrol effectively increased mitochondrial oxidative functions via increased pyruvate dehydrogenase complex (PDC) activity and downregulated pyruvate dehydrogenase kinase 4 (PDK4) expressions. Enhanced succinate dehydrogenase (SDH) activity was noticed following celastrol co-supplementation, leading to a steady establishment of the electrochemical gradient across mitochondrial membrane for ATP production and mitochondrial biogenesis. In conclusion, the current findings accentuate the therapeutic potential of celastrol against HFD-induced obese mice via enhanced glucose utilization and mitochondrial oxidative metabolism-mediated upregulation of PDC activity in the skeletal muscle.
    Keywords:  Celastrol; Glucose metabolism; Mitochondria; Obesity; Pyruvate dehydrogenase complex; Skeletal muscle
  8. Cell Metab. 2022 Jun 01. pii: S1550-4131(22)00189-9. [Epub ahead of print]
      Dietary fructose, especially in the context of a high-fat western diet, has been linked to type 2 diabetes. Although the effect of fructose on liver metabolism has been extensively studied, a significant portion of the fructose is first metabolized in the small intestine. Here, we report that dietary fat enhances intestinal fructose metabolism, which releases glycerate into the blood. Chronic high systemic glycerate levels induce glucose intolerance by slowly damaging pancreatic islet cells and reducing islet sizes. Our findings provide a link between dietary fructose and diabetes that is modulated by dietary fat.
    Keywords:  diabetes; dietary fat; fructose; glucose intolerance; glycerate; insulin; intestine; islet cell; metabolism; western diet
  9. Clin Perinatol. 2022 Jun;pii: S0095-5108(22)00020-3. [Epub ahead of print]49(2): 331-353
      Lipids are a major source of energy during the fetal/neonatal period. Most are received from the mother, transplacentally during the intrauterine period or via maternal milk after birth. However, in addition to the known nutritional roles, lipids are now known to bind a variety of cellular receptors to regulate specific patterns in metabolism and gene expression. The expression of these receptors is regulated by various genetic and environmental stimuli, and ligation can activate positive-feedback loops in the expression and the activity of downstream signaling pathways. The authors summarize the role of lipid ligands, cognate receptors, epigenetic regulation, and downstream signaling.
    Keywords:  Breast milk; DNA methylation; Extrauterine growth restriction; Fatty acids; Infant nutrition; Intrauterine growth restriction; Lipid receptors; Polyunsaturated fatty acids