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Diagnosis and Pathobiology
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
The epigenetic machinery can be separated into a number of interconnected components such as histone PTMs, DNA methylation (the most well-studied epigenetic alteration), noncoding RNAs (ncRNAs), and undercharacterized modifications (not discussed here) such as chromatin modifications, chromatin accessibility, histone (H) variants (e.g., H3.3, H2A.X, H2A.Z), and RNA modifications (e.g., N6-methyladenosine (m6A)) [296, 364, 367, 391, 393, 399, 402]. Many epigenetic modifications involve covalent bond modifications; however, the main noncovalent epigenetic mechanisms include incorporation of histone variants, nucleosome remodeling, and noncoding RNAs [369]. Chromatin structure and gene expression are regulated by specific amino acids of histone protein tails (consisting of 15–38 amino acids) that undergo various PTMs [366]. Due to the complex diversity among PTMs, the following are considered types of acylation: acetylation, propionylation, butyrylation, crotonylation, 2-hydroxy isobutyrylation, malonylation, succinylation, and glutarylation [403]. Ubiquitylation, sumoylation of lysine residues, and phosphorylation of serine (S) and threonine (T) residues, as well as formylation, O-GlcNAcylation, propionylation, adenosine diphosphate (ADP)-ribosylation, deamination, proline/aspartic acid isomerization, citrullination/eamination, biotinylation, and crotonylation, are reported histone modifications (>200 known modifications) that occur at more than 60 amino acid residues [296, 364, 386, 387, 394, 395].
Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
Variations in the levels of HAT and HDAC influence the compaction of chromatin, thereby causing improper expression of specific genes and culminating in genomic instability and epigenetic diseases (Park and Kim, 2020). Mechanistically, the amino groups of lysine residues in a protein undergoing different post-translational modifications such as acetylation, methylation, ubiquitination, sumoylation, propionylation, butyrylation, crotonylation, etc., thereby influencing the expression of genes (Seto and Yoshida, 2014). Class I HDACs play a prominent role in cell survival and proliferation, whereas Class II HDACs exhibit tissue-specific functions (Morris and Monteggia, 2013). For instance, HDAC1 knockout cells have a general proliferation and survival defect, despite increased levels of HDAC2 and HDAC3 activity. HDAC2 modulates transcriptional activity by regulating p53 binding. Abnormal HDACs play a key role in many human diseases including cancer, neurological and metabolic disorders, and inflammatory, cardiac and pulmonary diseases.
Modelling and Simulation of Nanosystems for Delivering Drugs to the Brain
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Tânia F. G. G. Cova, Sandra C.C. Nunes
Wu et al. [71] used MD to evaluate the potential of propionylated amylose to encapsulate hydrophobic drugs and release them by the interaction with POPE at concentrations similar to those found in the BBB. The release was promoted by the unfold of the helical structure of the amylose-hydrophobic drug complexes (see Scheme 1 in Ref. [71]). As hydrophobic model drug for the CNS the authors used propofol. The results showed that the nanoclusters exhibited high BBB permeability and specificity, rapid onset, short maintenance, quick recovery and reduced dosage. MD was used to inspect (i) drug encapsulation, (ii) the effect of propionylation on the stability of amylose-drug complexes and (iii) the release of propofol triggered by POPE solution, POPE and POPC bilayers. Results indicated that when nanoclusters contact with the membrane mimicking the BBB the helix unfolds and release the loaded drug, which crosses the BBB.
The role of pharmacogenomics in adverse drug reactions
Published in Expert Review of Clinical Pharmacology, 2019
Ramón Cacabelos, Natalia Cacabelos, Juan C. Carril
Histone deacetylation is involved in transcriptional repression and closed chromatin structure. In mammals, there are 18 HDACs, which are organized into 4 classes according to their homology to yeast. Histone deacetylation is catalyzed by these 4 classes of HDACs (class I, II, III, IV). Class I HDACs (HDAC1, 2, 3, and 8) are nuclear proteins; HDAC1 and HDAC2 are often found in transcriptional corepressor complexes (SIN3A, NuRD, CoREST), and HDAC3 is found in other complexes (SMRT/N-CoR); class II HDACs are subdivided into class IIa (HDAC4, 5,7, and 9), and IIb (HDAC6 and 10), which are located in the nucleus-cytoplasm interface and in the cytoplasm, respectively. Class III HDCAs belong to the sirtuin family, with nuclear (SIRT1, 2, 6, 7), mitochondrial (SIRT3, 4, 5), or cytoplasmic (SIRT1, 2) localization. Class IV HDAC (HDAC11) is a nuclear protein [27]. Histone deacetylases deacetylate histone and non-histone protein targets. Aberrant HDAC expression and function have been observed in several diseases. Eight types of short-chain Lys acylations have recently been identified on histones, including propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation. These histone modifications affect gene expression and are structurally and functionally different from the widely-studied histone Lys acetylation [68].
Proteomic insights into lysine acetylation and the implications for medical research
Published in Expert Review of Proteomics, 2019
Ramiro Alonso-Bastida, Sergio Encarnación-Guevara
However, in either case the inhibitors have the inconvenience of having a very global mechanism of action and thus affect all the acetylated target proteins and, in consequence; cytoskeleton organization, autophagy, RNA processing and stability, protein folding, protein aggregation, protein degradation and protein-protein interactions in almost every cell in the body. They even affect other PTMs like succinylation, propionylation, ubiquitylation, and phosphorylation [4]. As a consequence, a current goal is the development of new inhibitors that could be combined with other medications and/or radiotherapy to improve their action over those achieved with the inhibitor alone. This could lead to molecules with defined targets, and enhanced therapeutic effects with no or minimal side effects.
Epigenetic Regulatory Enzymes: mutation Prevalence and Coexistence in Cancers
Published in Cancer Investigation, 2021
Amit Sharma, Hongde Liu, Martina C. Herwig-Carl, Tikam Chand Dakal, Ingo G H Schmidt-Wolf
DNA methylation alone is often coupled with other epigenetic modifications in order to jointly regulate gene silencing. Therefore, other processes are also required for the organization and dynamics of genome. Nearly, 147 base pairs of DNA wrapped around an octamer of four core histones, (H2A, H2B, H3, and H4), and the linker histone H1 to form the basic architecture (as nucleosome) of chromatin. The histones play a very significant role and act as second key epigenetic mechanism by having modifications on the histone terminal tails with profound effects on gene transcription, DNA repair and replication (Reviewed in Allis et al (75)). To date, several types of histone modifications [acetylation, methylation (lysine, arginine), phosphorylation (serine, threonine), ubiquitination, sumoylation, ADP-ribosylation, deimination, proline isomerism, propionylation, butyrylation, crotonylation etc.] have been known. These modifications are precisely added or removed at the histone amino acid residues by specific set of enzymes e.g. acetyl groups are added to lysine residues of histones H3 and H4 by histone acetyltransferases (HAT) and subsequently removed by deacetylases (HDAC). There are numerous reports showing involvement of mutations in HAT genes (EP300, p300, CBP, MOZ, and MORF) in many diseases, including cancers (76,77). The mutations in the CREBBP gene encoding histone acetyltransferase activity (for H3K18), have been reported in acute lymphoblastic leukemia and Rubinstein–Taybi Syndrome (78,79). The aberrant expression of HDACs has been shown in variety of cancers (gastric, ovarian, breast, lung, colorectal) and other diseases such as childhood acute lymphoblastic leukemia and mood disorder, idiopathic pulmonary fibrosis, Hodgkin's lymphoma (80–88).