n -Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells
TL;DR: Rapid, dramatic, and reversible increases in histone acetylation in the presence of n-butyrate are described.
Abstract: LEDER and Leder1 have reported that low concentrations of n-butyrate cause Friend erythroleukaemia cells to begin globin synthesis. Apparently n-butyrate can reverse that part of viral transformation which prevents the expression of differentiation in these cells. Prasad and Sinha2 have summarised the effects of n-butyrate on neuroblastoma, HeLa, and other cell types. They and others3–10 have seen reversible inhibition of proliferation, decrease of DNA content, morphological modifications, and increases in the production of specific enzymes, such as adenylate cyclase, alkaline phosphatase, and a sialyltransferase. The present paper describes rapid, dramatic, and reversible increases in histone acetylation in the presence of n-butyrate.
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TL;DR: Recent advances in the understanding of the molecular events that underlie the anticancer effects of HDAC inhibitors are summarized and how such information could be used in optimizing the development and application of these agents in the clinic, either as monotherapies or in combination with other anticancer drugs are discussed.
Abstract: Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addition, the activity of non-histone proteins can be regulated through HDAC-mediated hypo-acetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. However, such studies have also indicated that the effects of HDAC inhibitors could be considerably broader and more complicated than originally understood. Here we summarize recent advances in the understanding of the molecular events that underlie the anticancer effects of HDAC inhibitors, and discuss how such information could be used in optimizing the development and application of these agents in the clinic, either as monotherapies or in combination with other anticancer drugs.
2,777 citations
Cites background from "n -Butyrate causes histone modifica..."
...It was subsequently discovered that butyrate induced histone hyperacetylatio...
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TL;DR: This review will provide potential mechanistic explanations for the association between EMT induction and the emergence of CSCs, and highlight recent studies implicating the function of TGF-β-regulated noncoding RNAs in driving EMT and promoting CSC self-renewal.
Abstract: Tumors are cellularly and molecularly heterogeneous, with subsets of undifferentiated cancer cells exhibiting stem cell-like features (CSCs). Epithelial to mesenchymal transitions (EMT) are transdifferentiation programs that are required for tissue morphogenesis during embryonic development. The EMT process can be regulated by a diverse array of cytokines and growth factors, such as transforming growth factor (TGF)-β, whose activities are dysregulated during malignant tumor progression. Thus, EMT induction in cancer cells results in the acquisition of invasive and metastatic properties. Recent reports indicate that the emergence of CSCs occurs in part as a result of EMT, for example, through cues from tumor stromal components. Recent evidence now indicates that EMT of tumor cells not only causes increased metastasis, but also contributes to drug resistance. In this review, we will provide potential mechanistic explanations for the association between EMT induction and the emergence of CSCs. We will also highlight recent studies implicating the function of TGF-β-regulated noncoding RNAs in driving EMT and promoting CSC self-renewal. Finally we will discuss how EMT and CSCs may contribute to drug resistance, as well as therapeutic strategies to overcome this clinically.
2,342 citations
Cites result from "n -Butyrate causes histone modifica..."
...This can be reinforced by the results with HDAC inhibitors, such as n-butyrate, which can induce the differentiation of erythroleukemic cells (Leder et al., 1975; Riggs et al., 1977)....
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TL;DR: Results clearly indicate that TSA is a potent and specific inhibitor of the histone deacetylase and that the in vivo effect of TSA on cell proliferation and differentiation can be attributed to the inhibition of the enzyme.
1,897 citations
TL;DR: An overview of microbial SCFAs production and their effects on the intestinal mucosa with specific emphasis on their relevance for Inflammatory Bowel Diseases is presented and the therapeutic potential ofSCFAs for IBD is discussed.
Abstract: Ulcerative colitis (UC) and Crohn's disease (CD), collectively known as Inflammatory Bowel Diseases (IBD), are caused by a complex interplay between genetic, immunologic, microbial and environmental factors. Dysbiosis of the gut microbiome is increasingly considered to be causatively related to IBD and is strongly affected by components of a Western life style. Bacteria that ferment fibers and produce short chain fatty acids (SCFAs) are typically reduced in mucosa and feces of patients with IBD, as compared to healthy individuals. SCFAs, such as acetate, propionate and butyrate, are important metabolites in maintaining intestinal homeostasis. Several studies have indeed shown that fecal SCFAs levels are reduced in active IBD. SCFAs are an important fuel for intestinal epithelial cells and are known to strengthen the gut barrier function. Recent findings, however, show that SCFAs, and in particular butyrate, also have important immunomodulatory functions. Absorption of SCFAs is facilitated by substrate transporters like MCT1 and SMCT1 to promote cellular metabolism. Moreover, SCFAs may signal through cell surface G-protein coupled receptors (GPCRs), like GPR41, GPR43, and GPR109A, to activate signaling cascades that control immune functions. Transgenic mouse models support the key role of these GPCRs in controlling intestinal inflammation. Here, we present an overview of microbial SCFAs production and their effects on the intestinal mucosa with specific emphasis on their relevance for IBD. Moreover, we discuss the therapeutic potential of SCFAs for IBD, either applied directly or by stimulating SCFAs-producing bacteria through pre- or probiotic approaches.
1,732 citations
TL;DR: The development of small-molecule HDAC inhibitors and their use in the laboratory, in preclinical models and in the clinic are highlighted.
Abstract: Histone deacetylases (HDACs) are a class of epigenetic enzymes that remove acetyl groups from lysine residues on histones and other proteins. In this Review, the authors highlight the role of HDACs in cancer, neurological diseases and immune disorders, and discuss the development of small-molecule inhibitors. Epigenetic aberrations, which are recognized as key drivers of several human diseases, are often caused by genetic defects that result in functional deregulation of epigenetic proteins, their altered expression and/or their atypical recruitment to certain gene promoters. Importantly, epigenetic changes are reversible, and epigenetic enzymes and regulatory proteins can be targeted using small molecules. This Review discusses the role of altered expression and/or function of one class of epigenetic regulators — histone deacetylases (HDACs) — and their role in cancer, neurological diseases and immune disorders. We highlight the development of small-molecule HDAC inhibitors and their use in the laboratory, in preclinical models and in the clinic.
1,261 citations
References
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TL;DR: Studies using a variety of analogues and metabolites suggest that the structural features of butyric acid are rather stringently required for induction of erythroid differentiation.
630 citations
TL;DR: This work has made use of the observation that free ribosomes from hamster cells form dimers in conditions where mouse free Ribosomes remain as monomers, dimers or as both to determine whether mouse-hamster hybrid cells contain freeribosomes as monomer, dimer or both.
Abstract: ONLY mouse 28S ribosomal RNA (rRNA) can be detected in mouse-human hybrid cells1. Because these cells contain as many as thirty-five human chromosomes, including those believed to have ribosomal RNA genes, it has been suggested that the transcription of human ribosomal RNA genes may be repressed. Similar studies have not been performed with mouse-hamster hybrid cells because hamster and mouse 28S rRNAs have only a very small difference in their electro-phoretic mobilities2. We have now made use of the observation that free ribosomes (not engaged in translation) from hamster cells form dimers in conditions where mouse free ribosomes remain as monomers3 to determine whether mouse-hamster hybrid cells contain free ribosomes as monomers, dimers or as both.
539 citations
TL;DR: The structural function of histones is to organize the long, fibrillar molecules of DNA into a more compact form, achieved, in part, by electrostatic interactions between the positively charged basic amino acids in the histone polypeptide chains and the negatively charged phosphate groups of DNA.
Abstract: deoxyribonucleic acid of the somatic cells of higher organisms occurs in association with small basic proteins called histones. In most cell types histones can be grouped into five major classes differing in size, positive charge, and amino acid composition. The primary structures of homologous histones from widely divergent species give evidence of remarkable evolutionary stability, particularly the arginine-rich histones, H3 and H4. Histones H2a and H2b (1) show slightly less evolutionary stability in their amino acid sequences, while histone H 1 varies to the greatest extent (la). The structural function of histones is to organize the long, fibrillar molecules of DNA into a more compact form. This organization is achieved, in part, by electrostatic interactions between the positively charged basic amino acid residues in the histone polypeptide chains and the negatively charged phosphate groups of DNA. Current evidence favors a cooperative interaction in which four of the five major types of histones interact with each other in specific ways and in stoichiometric proportions to form multimeric protein complexes (2). The fundamental unit of eukaryotic chromatin may be visualized as small nucleoprotein particles (3-5) [called nu bodies (4) or PS-particles (5)] along the DNA molecule, in which each histone complex is enveloped by the DNA strand (6). In the assembly of such particles and in their attachment to DNA, it is likely that particular regions of the histone polypeptide chains have different functions. Histone structures usually reveal a characteristic clustering of their basic amino acidsarginine, lysine, and histidine-thus generating regions of high positive charge (Fig. 1). This positively charged region is most
401 citations
TL;DR: A method for the clonal analysis of murine erythroleukemia cells has been developed which allows the precise characterization of the number of progeny produced by each cell and the degree of differentiation of each progeny cell, and it is observed that the commitment decision limits the subsequent proliferative capacity of the cell to four additional cell divisions.
339 citations
TL;DR: Sodium butyrate appears to have properties of a good chemotherapeutic agent for neuroblastoma tumors because the treatment of Neuroblastoma cells in culture causes cell death and “differentiation”; however, it is either innocuous or produces reversible morphological and biochemical alterations in other cell types.
Abstract: Sodium butyrate produces reversible changes in morphology, growth rate, and enzyme activities of several mammalian cell types in culture. Some of these changes are similar to those produced by agents which increase the intracellular level of adenosine 3′,5′-cyclic monophosphate (cAMP) or by analogs of cAMP. Sodium butyrate increases the intracellular level of cAMP by about two fold in neuroblastoma cells; therefore, some of the effects of sodium butyrate on these cells may in part be mediated by cAMP. Sodium butyrate appears to have properties of a good chemotherapeutic agent for neuroblastoma tumors because the treatment of neuroblastoma cells in culture causes cell death and “differentiation”; however, it is either innocuous or produces reversible morphological and biochemical alterations in other cell types.
314 citations