scholarly journals Characterization of Histone Deacetylase Mechanisms in Cancer Development

2021 ◽  
Vol 11 ◽  
Author(s):  
Rihan Hai ◽  
Liuer He ◽  
Guang Shu ◽  
Gang Yin
Keyword(s):  
Histone Deacetylases ◽  
Histone Acetyltransferases ◽  
Cancer Development ◽  
Dynamic Processes ◽  
Tumour Suppressor Genes ◽  
Nonhistone Proteins ◽  
Post Translational Modifications ◽  
Physiological Processes ◽  
Lysine Residues

Over decades of studies, accumulating evidence has suggested that epigenetic dysregulation is a hallmark of tumours. Post-translational modifications of histones are involved in tumour pathogenesis and development mainly by influencing a broad range of physiological processes. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are pivotal epigenetic modulators that regulate dynamic processes in the acetylation of histones at lysine residues, thereby influencing transcription of oncogenes and tumour suppressor genes. Moreover, HDACs mediate the deacetylation process of many nonhistone proteins and thus orchestrate a host of pathological processes, such as tumour pathogenesis. In this review, we elucidate the functions of HDACs in cancer.

scholarly journals Comprehensive Analysis of the Histone Deacetylase Gene Family in Chinese Cabbage (Brassica rapa): From Evolution and Expression Pattern to Functional Analysis of BraHDA3

Agriculture ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 244
Author(s):  
Seung Hee Eom ◽  
Tae Kyung Hyun
Keyword(s):  
Functional Analysis ◽  
Brassica Rapa ◽  
Chinese Cabbage ◽  
Stress Responses ◽  
Histone Deacetylases ◽  
Expression Patterns ◽  
Evolutionary Relationship ◽  
Gene Families ◽  
Physiological Processes ◽  
Lysine Residues

Histone deacetylases (HDACs) are known as erasers that remove acetyl groups from lysine residues in histones. Although plant HDACs play essential roles in physiological processes, including various stress responses, our knowledge concerning HDAC gene families and their evolutionary relationship remains limited. In Brassica rapa genome, we identified 20 HDAC genes, which are divided into three major groups: RPD3/HDA1, HD2, and SIR2 families. In addition, seven pairs of segmental duplicated paralogs and one pair of tandem duplicated paralogs were identified in the B. rapa HDAC (BraHDAC) family, indicating that segmental duplication is predominant for the expansion of the BraHDAC genes. The expression patterns of paralogous gene pairs suggest a divergence in the function of BraHDACs under various stress conditions. Furthermore, we suggested that BraHDA3 (homologous of Arabidopsis HDA14) encodes the functional HDAC enzyme, which can be inhibited by Class I/II HDAC inhibitor SAHA. As a first step toward understanding the epigenetic responses to environmental stresses in Chinese cabbage, our results provide a solid foundation for functional analysis of the BraHDAC family.

scholarly journals Bromodomains as therapeutic targets

2011 ◽  
Vol 13 ◽  
Author(s):  
Susanne Muller ◽  
Panagis Filippakopoulos ◽  
Stefan Knapp
Keyword(s):  
Squamous Cell Carcinoma ◽  
Drug Development ◽  
Cell Carcinoma ◽  
Protein Interaction ◽  
Histone Deacetylases ◽  
Histone Acetyltransferases ◽  
Reading Process ◽  
Post Translational Modification ◽  
Disease Biology ◽  
Lysine Residues

Acetylation of lysine residues is a post-translational modification with broad relevance to cellular signalling and disease biology. Enzymes that ‘write’ (histone acetyltransferases, HATs) and ‘erase’ (histone deacetylases, HDACs) acetylation sites are an area of extensive research in current drug development, but very few potent inhibitors that modulate the ‘reading process’ mediated by acetyl lysines have been described. The principal readers of ɛ-N-acetyl lysine (Kac) marks are bromodomains (BRDs), which are a diverse family of evolutionary conserved protein-interaction modules. The conserved BRD fold contains a deep, largely hydrophobic acetyl lysine binding site, which represents an attractive pocket for the development of small, pharmaceutically active molecules. Proteins that contain BRDs have been implicated in the development of a large variety of diseases. Recently, two highly potent and selective inhibitors that target BRDs of the BET (bromodomains and extra-terminal) family provided compelling data supporting targeting of these BRDs in inflammation and in an aggressive type of squamous cell carcinoma. It is likely that BRDs will emerge alongside HATs and HDACs as interesting targets for drug development for the large number of diseases that are caused by aberrant acetylation of lysine residues.

scholarly journals Kinetic Characterization of Human Histone Deacetylase 8 With Medium-Chain Fatty Acyl Lysine

2021 ◽  
Vol 14 ◽  
pp. 251686572110656
Author(s):  
Harrison Yoo ◽  
Gregory A Polsinelli
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Decanoic Acid ◽  
Fatty Acyl ◽  
Peptide Substrate ◽  
Medium Chain ◽  
Histone Deacetylase 8 ◽  
Lysine Residues

Histone deacetylases (HDACs) catalyze the removal of Ɛ-acetyl-lysine residues of histones via hydrolysis. Removal of acetyl groups results in condensation of chromatin structure and alteration of gene expression by repression. HDACs are considered targets for the treatment of cancer due to their role in regulating transcription. HDAC8 inhibition may be an important anti-proliferative factor for histone deacetylase inhibitors on cancer cells and may give rise to the progression of apoptosis. HDAC8 activity was analyzed with various peptides where the target lysine is modified with medium-chain fatty acyl group. Kinetic data were determined for each p53 peptide substrate. The results suggest that there was HDAC8 deacetylase activity on peptide substrate as well as deacylase activity with acylated peptide substrate variants. HDAC8 inhibition by hexanoic and decanoic acid was also examined. The Ki for hexanoic and decanoic acid were determined to be 2.35 ± 0.341 and 4.48 ± 0.221 mM, respectively.

scholarly journals A class of their own: exploring the nondeacetylase roles of class IIa HDACs in cardiovascular disease

2016 ◽  
Vol 311 (1) ◽  
pp. H199-H206 ◽  
Author(s):  
Lillianne H. Wright ◽  
Donald R. Menick
Keyword(s):  
Histone Deacetylases ◽  
Translational Regulation ◽  
Protein Stabilization ◽  
Therapeutic Interventions ◽  
Cardiac Events ◽  
Nonhistone Proteins ◽  
The Past ◽  
Binding Partners ◽  
Lysine Residues ◽  
Class Iia Hdacs

Histone deacetylases (HDACs) play integral roles in many cardiovascular biological processes ranging from transcriptional and translational regulation to protein stabilization and localization. There are 18 known HDACs categorized into 4 classes that can differ on the basis of substrate targets, subcellular localization, and regulatory binding partners. HDACs are classically known for their ability to remove acetyl groups from histone and nonhistone proteins that have lysine residues. However, despite their nomenclature and classical functions, discoveries from many research groups over the past decade have suggested that nondeacetylase roles exist for class IIa HDACs. This is not surprising given that class IIa HDACs have, for example, relatively poor deacetylase capabilities and are often shuttled in and out of nuclei upon specific pathological and nonpathological cardiac events. This review aims to consolidate and elucidate putative nondeacetylase roles for class IIa HDACs and, where possible, highlight studies that provide evidence for their noncanonical roles, especially in the context of cardiovascular maladies. There has been great interest recently in exploring the pharmacological regulators of HDACs for use in therapeutic interventions for treating cardiovascular diseases and inflammation. Thus it is of interest to earnestly consider nonenzymatic and or nondeacetylase roles of HDACs that might be key in potentiating or abrogating pathologies. These noncanonical HDAC functions may possibly yield new mechanisms and targets for drug discovery.

scholarly journals The function of histone acetylation in cervical cancer development

2019 ◽  
Vol 39 (4) ◽  
Author(s):  
Shanshan Liu ◽  
Weiqin Chang ◽  
Yuemei Jin ◽  
Chunyang Feng ◽  
Shuying Wu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Histone Acetylation ◽  
Gene Sequence ◽  
Hpv Infection ◽  
Cancer Development ◽  
Post Translational Modifications ◽  
Cellular Life ◽  
Lysine Residues ◽  
Cervical Cancer Development ◽  
Gene Expression Levels

AbstractCervical cancer is the fourth most common female cancer in the world. It is well known that cervical cancer is closely related to high-risk human papillomavirus (HPV) infection. However, epigenetics has increasingly been recognized for its role in tumorigenesis. Epigenetics refers to changes in gene expression levels based on non-gene sequence changes, primarily through transcription or translation of genes regulation, thus affecting its function and characteristics. Typical post-translational modifications (PTMs) include acetylation, propionylation, butyrylation, malonylation and succinylation, among which the acetylation modification of lysine sites has been studied more clearly so far. The acetylation modification of lysine residues in proteins is involved in many aspects of cellular life activities, including carbon metabolism, transcriptional regulation, amino acid metabolism and so on. In this review, we summarize the latest discoveries on cervical cancer development arising from the aspect of acetylation, especially histone acetylation.

Collagen hydroxylysine glycosylation: non-conventional substrates for atypical glycosyltransferase enzymes

2021 ◽  
Author(s):  
Francesca De Giorgi ◽  
Marco Fumagalli ◽  
Luigi Scietti ◽  
Federico Forneris
Keyword(s):  
Current Knowledge ◽  
Three Dimensional ◽  
Major Constituent ◽  
Post Translational Modifications ◽  
Current State ◽  
Lysine Residues ◽  
Collagen Molecules ◽  
Triple Helices ◽  
The Impact

Collagen is a major constituent of the extracellular matrix (ECM) that confers fundamental mechanical properties to tissues. To allow proper folding in triple-helices and organization in quaternary super-structures, collagen molecules require essential post-translational modifications (PTMs), including hydroxylation of proline and lysine residues, and subsequent attachment of glycan moieties (galactose and glucose) to specific hydroxylysine residues on procollagen alpha chains. The resulting galactosyl-hydroxylysine (Gal-Hyl) and less abundant glucosyl-galactosyl-hydroxylysine (Glc-Gal-Hyl) are amongst the simplest glycosylation patterns found in nature and are essential for collagen and ECM homeostasis. These collagen PTMs depend on the activity of specialized glycosyltransferase enzymes. Although their biochemical reactions have been widely studied, several key biological questions about the possible functions of these essential PTMs are still missing. In addition, the lack of three-dimensional structures of collagen glycosyltransferase enzymes hinders our understanding of the catalytic mechanisms producing this modification, as well as the impact of genetic mutations causing severe connective tissue pathologies. In this mini-review, we summarize the current knowledge on the biochemical features of the enzymes involved in the production of collagen glycosylations and the current state-of-the-art methods for the identification and characterization of this important PTM.

scholarly journals Structural characterization of human and bovine lung surfactant protein D

1999 ◽  
Vol 343 (3) ◽  
pp. 645-652 ◽  
Author(s):  
Rikke LETH-LARSEN ◽  
Uffe HOLMSKOV ◽  
Peter HØJRUP
Keyword(s):  
Lung Surfactant ◽  
Surfactant Protein ◽  
Glycosylation Site ◽  
Surfactant Protein D ◽  
Post Translational Modifications ◽  
Single Polypeptide Chain ◽  
Lysine Residues ◽  
Lung Surfactant Protein ◽  
Single Polypeptide

Human and bovine surfactant proteins D (SP-D) were purified from late amniotic fluid and bronchioalveolar lavage on the basis of its Ca2+-dependent affinity for maltose. The molecular mass of a trimeric subunit was determined by matrix-assisted laser desorption ionization MS to lie in the range 115-125 kDa for human SP-D and 110-123 kDa for bovine SP-D. A single polypeptide chain was determined at 37-41 and 36-40 kDa for the human and bovine species respectively. The major parts of the primary structures of both SP-D molecules were determined by a combination of MS and Edman degradation. The heterogeneity in SP-D was caused mainly by a high number of post-translational modifications in the collagen-like region. Proline and lysine residues were partly hydroxylated and lysine residues were further O-glycosylated with the disaccharide galactose-glucose. A partly occupied N-linked glycosylation site was characterized in human SP-D. The carbohydrate was determined as a complex type bi-antennary structure, with a small content of mono-antennary and tri-antennary structures. No sialic acid residues were present on the glycan, but some had an attached fucose and/or an N-acetylglucosamine residue linked to the core. Bovine SP-D was determined as having a similar structure.

scholarly journals Acetylation & Co: an expanding repertoire of histone acylations regulates chromatin and transcription

2019 ◽  
Vol 63 (1) ◽  
pp. 97-107 ◽  
Author(s):  
Claire E. Barnes ◽  
David M. English ◽  
Shaun M. Cowley
Keyword(s):  
Histone Deacetylases ◽  
Chemical Properties ◽  
Histone Acetyltransferases ◽  
Lysine Acetylation ◽  
Active Chromatin ◽  
Eukaryotic Species ◽  
Lysine Residues ◽  
Global Mapping ◽  
Transcriptional Start Sites ◽  
Gain Access

Abstract Packaging the long and fragile genomes of eukaryotic species into nucleosomes is all well and good, but how do cells gain access to the DNA again after it has been bundled away? The solution, in every species from yeast to man, is to post-translationally modify histones, altering their chemical properties to either relax the chromatin, label it for remodelling or make it more compact still. Histones are subject to a myriad of modifications: acetylation, methylation, phosphorylation, ubiquitination etc. This review focuses on histone acylations, a diverse group of modifications which occur on the ε-amino group of Lysine residues and includes the well-characterised Lysine acetylation. Over the last 50 years, histone acetylation has been extensively characterised, with the discovery of histone acetyltransferases (HATs) and histone deacetylases (HDACs), and global mapping experiments, revealing an association of hyperacetylated histones with accessible, transcriptionally active chromatin. More recently, there has been an explosion in the number of unique short chain ‘acylations’ identified by MS, including: propionylation, butyrylation, crotonylation, succinylation, malonylation and 2-hydroxyisobutyrylation. These novel modifications add a range of chemical environments to histones, and similar to acetylation, appear to accumulate at transcriptional start sites and correlate with gene activity.

scholarly journals Hat1 acetylates histone H4 and modulates the transcriptional program in Drosophila embryogenesis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Júlia Varga ◽  
Szabina Korbai ◽  
Alexandra Neller ◽  
Nóra Zsindely ◽  
László Bodai
Keyword(s):  
Rna Seq ◽  
Histone H4 ◽  
Loss Of Function ◽  
Post Translational Modifications ◽  
Cell Functions ◽  
Drosophila Embryogenesis ◽  
Developmental Program ◽  
Lysine Residues ◽  
Transcriptional Changes

AbstractPost-translational modifications of histone proteins play a pivotal role in DNA packaging and regulation of genome functions. Histone acetyltransferase 1 (Hat1) proteins are conserved enzymes that modify histones by acetylating lysine residues. Hat1 is implicated in chromatin assembly and DNA repair but its role in cell functions is not clearly elucidated. We report the generation and characterization of a Hat1 loss-of-function mutant in Drosophila. Hat1 mutants are viable and fertile with a mild sub-lethal phenotype showing that Hat1 is not essential in fruit flies. Lack of Hat1 results in the near complete loss of histone H4 lysine (K) 5 and K12 acetylation in embryos, indicating that Hat1 is the main acetyltransferase specific for these marks in this developmental stage. We found that Hat1 function and the presence of these acetyl marks are not required for the nuclear transport of histone H4 as histone variant His4r retained its nuclear localization both in Hat1 mutants and in His4r-K5R-K12R double point mutants. RNA-seq analysis of embryos indicate that in Hat1 mutants over 2000 genes are dysregulated and the observed transcriptional changes imply a delay in the developmental program of gene expression.

Sign in / Sign up

Export Citation Format

Share Document