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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
This class is comprised of one HDAC enzyme, i.e. HDAC11 (Figure 8.1B) (Seto and Yoshida, 2014). The HDAC11 uniquely shares sequence homology with the catalytic domains of both Class I and II HDACs. HDAC11 regulates the protein stability of DNA replication factor CDT1 (chromatin licensing and DNA replication factor 1) and the expression of interleukin 10 (IL-10) (Glozak and Seto, 2009). Further studies are warranted to delineate the structural and functional properties of HDAC11.
New Biological Targets for the Treatment of Leishmaniasis
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Fabrizio Carta, Andrea Angeli, Christian D.-T. Nielsen, Claudiu T. Supuran, Agostino Cilibrizzi
On the basis of structural differences, HDACs are grouped into two main families, in turn composed by a number of subfamilies: (1) zinc-dependent histone deacetylases, generically referred as histone deacetylases or metal-dependent histone deacetylases, i.e., class I (HDACs 1, 2, 3 and 8), class IIa (HDACs 4, 5, 7, 9), class IIb (HDACs 6, 10) and class IV (HDAC11); (2) NAD-dependent histone deacetylases (also named sirtuins, SIRT), i.e., class III HDAC.
DNA Methylation and Epigenetics: New Developments in Biology and Treatment
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Jesus Duque, Michael Lübbert, Mark Kirschbaum
Deacetylation is accomplished via a large group of enzymes comprising, at this time, four groups (based on homology to yeast proteins) of HDACs, with the class I HDACs, similar to Rpd3, being the dominant group of nuclear HDACs, class II, similar to HdaI, having cytoplasmic activity as well in their role as protein acetylases, the class III HDACs, the Sir2 homologs, having very different structure and activity, now generally referred to as Sirtuins, and the class IV HDAC11. In order to understand their manifold activities, it is important to recognize that HATs and HDACs (as well as many of the other enzymes which act in an epigenetic manner) tend to be recruited to large complexes through which they exert their action, with the presence of chromodomains and bromodomains, domains that bind methyl-lysine and acetyl-lysine, respectively (55). HDAC 1 and 2 complex with mSin3A to form a repressor complex (56,57), and complex with NCoR and SMRT to act as nuclear hormone receptor corepressors (58,59). Complexes seem to facilitate the activity of other complexes, so that the various SWI/SNF chromatin-remodeling complexes act to recruit HAT complexes leading to acetylation (60–62) and retinoblastoma-E2F complexes recruit HDACs as part of their repressive activity (63). Interestingly, SWI/SNF complex activity has been shown to bring about loss of DNA methylation as well at targets such as CD44 and E-cadherin (64), introducing further levels of network-like complexity to the interplay between the various epigenetic enzymes. Thus, it becomes less surprising that treatment with the hydroxamate HDAC inhibitor (HDACi) LBH589 can lead to decreased histone methylation via the disruption of the polycomb repressor complex 2 (65) or that valproic acid, a drug used for years as an antiepileptic agent and recently found to have HDAC activity (66), can lead to DNA demethylation (67). This may help explain the dramatic activity of HDACi, such as vorinostat and LBH589, as single agents particularly in lymphoid malignancies, with single agent activity seen in Hodgkin’s lymphoma, diffuse large B cell lymphoma, ALL, and indolent lymphomas (68–71, Kirschbaum, personal communication) (Fig 2).
Givinostat: an emerging treatment for polycythemia vera
Published in Expert Opinion on Investigational Drugs, 2020
Helen T. Chifotides, Prithviraj Bose, Srdan Verstovsek
The interest in HDACs as novel targets for drug development stems from the pleiotropic roles they play in neoplastic cells [56], including their regulatory role in the expression of numerous genes (for example, HDACs modulate the expression of pro-apoptotic or tumor suppressor genes), and aberrant activity in many cancer types [57], including MPNs. Besides universally activating the JAK/STAT pathway, JAK2V617F can promote myeloproliferation by phosphorylating histone H3 after translocating to the nucleus [13,58]. This action, in turn, impairs the binding of HP1α to chromatin, ultimately promoting the transcription of thousands of genes. Furthermore, significantly upregulated HDAC expression [57] has been reported in patients with chronic MPNs; two studies showed that HDAC4, HDAC5, HDAC6, HDAC9, and HDAC11 were elevated in patients with PV [59,60]. Splenomegaly was associated with increased levels of HDACs in MF patients [60], and progressive increase of HDAC6 levels was reported during disease evolution from PV to MF [59]. A recent study demonstrated that HDAC11 is required for the proliferation and survival of oncogenic JAK-driven human and mouse MPN cell lines and MPN patient specimens [61]. Collectively, the involvement of HDACs and epigenetic dysregulation in MPN pathogenesis [62–65] together with the critical role of JAK2 and its downregulation by HDAC6 inhibitors, via interference with acetylation of the chaperone protein heat shock protein 90 (HSP90) [66], spurred interest in exploring HDAC inhibitors as a novel treatment for MPNs [57,67–70].
The role of myeloid-derived suppressor cells in the pathogenesis of rheumatoid arthritis; anti- or pro-inflammatory cells?
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Misagh Rajabinejad, Farhad Salari, Ali Gorgin Karaji, Alireza Rezaiemanesh
HMGB1 can increase the production of IL-10 from MDSC, enhances MDSC cross-talk with macrophages, and promotes the MDSC-mediated downregulation of the L-selectin expression on the naive T cells. Histone deacetylase 11 (HDAC11) is another factor that regulates MDSC suppressive potency through IL-10 production, and HDAC11-knockout mice have higher levels and more suppressive MDSC, suggesting that HDAC11 is a negative regulator for the development of MDSC [60]. Furthermore, IL-4Rα (CD124) and its signalling pathway through STAT6, a transcription factor for both IL-4 and IL-13 signalling, have an important role in the MDSCs activation. IL-13 and IL-4 can upregulate the activity of Arg1, which increases the suppressive function of MDSCs [61,62]. In addition, IFN-γ-mediated signalling (by STAT1) is involved in the upregulation of Arg1 and iNOS expression in MDSCs [63]. PGE2 also drives the suppressive potency of MDSC by increasing the expression of Arg1 [64]. IL-1β, IL-6, and IL-17 also can induce suppressive potency of these cells, in addition to the role involved in the expansion of MDSCs [65,66]. Moreover, the complement system can also be effective in MDSC activity. for example, complement component C5a can drive accumulation and activation of MDSCs [67].
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].