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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
Modification of histones by acetylation is one of the most common post-translational modifications, and was first defined in 1960. Inoue and Fujimoto (1969) observed that acetyl groups are removed from the histones in a calf thymus extract. Subsequently, during the 1970s, several studies identified HDAC activity in tissues; and in 1996, the first bona fide histone deacetylase, i.e. HDAC1, was isolated and cloned (Taunton et al., 1996). HDACs remove acetyl groups from histones, resulting in a more condensed, transcriptionally inactive chromatin state. Inactive chromatin causes the downregulation of tumor suppressor genes such as p21, p27, p53 and (retinoblastoma protein) Rb, etc., leading to uncontrolled cell proliferation, survival, migration and differentiation (Figure 8.2) (Parbin et al., 2014). Therefore, hyper-active HDACs are reported to induce cancer (Li and Seto, 2016). A number of studies further dissected the biochemical characterization of the histone deacetylase and elucidated structure–activity relationships.
The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Histone modifications occur in tumor cells in different types of histone proteins, their variants and on individual residues within them. These involve modifications to chemical functional groups, including variations to the degree of methylation. In general, acetylation of histones signifies transcription activation, while the effect of methylation of histones is less specific and dependent on the amino acid type and position of the histone tail. The generally accepted mechanism for enhanced gene transcription through acetylation of lysine residues is that nonacetylated lysine residues possess side-chains terminating in positively charged (i.e., protonated) amino groups which keep the chromatin condensed through electrostatic charges. Once acetylated, the positive charge is lost, and the chromatin opens (i.e., de-condenses), thus exposing the DNA to transcription-promoting proteins including transcription factors. Also, the pattern of expression of histone-modifying enzymes is distinct in tumor versus healthy cells. These modifications to histone proteins can be reliably and specifically detected by mass spectrometry techniques. For example, overexpression of the histone demethylase PLU-1 has been detected in breast cancer cells, and variations of expression of the histone deacetylase HDAC1 has been detected in hematological, colon, and endometrial cancer cells.
Tyrosine Phosphatases as New Treatment Targets in Acute Myeloid Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
I. Hubeek, K. Hoorweg, J. Cloos, Gertjan J. L. Kaspers
In hematopoietic malignancies, SHP-1 expression is often lost due to the methylation of the promoter region of PTPN6 or a posttranscriptional block of SHP-1 protein synthesis (57,69). PTPN6 was for the first time shown to be methylated in T-cell lymphoma cell lines (65). Hypermethylation of PTPN6 was also shown for anaplastic large-cell lymphoma, different leukemia forms, and in multiple myeloma (70,71). A study of Oka et al. (2002) describes that 62.5% (5/8) of acute lymphoblastic leukemia (ALL) 90.0% (9/10) of AML, and 100.0% (11/11) of CML patient specimens showed methylation at the CpG island of the PTPN6 promoter (70). Thus, loss of SHP-1 in hematopoietic malignancies leads to overactive signaling pathways involved in survival and growth. Zhang et al. (2005) identified a protein complex that binds to the PTPN6 promoter and induces epigenetic silencing. This complex includes signal transducer and activator of transcription 3 (STAT3) and DNA methyltransferase 1, both of which are thought to be crucial for the silencing of PTPN6. The involvement of STAT3, DNMT1, and, apparently, HDAC1 in the epigenetic silencing of the SHP-1 gene may have therapeutic implications. Demethylating agents and HDAC inhibitors are being evaluated in various malignancies with promising results (72).
Histone deacetylase inhibitors as a potential new treatment for psoriatic disease and other inflammatory conditions
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Jehan Mohammad Nazri, Katerina Oikonomopoulou, Elvin D. de Araujo, Dziyana Kraskouskaya, Patrick T. Gunning, Vinod Chandran
As mentioned previously, HDACs are enzymes that function to remove acetyl groups from lysine residues of proteins in a process called deacetylation. These proteins, also known as substrates, can be classified as either histone or non-histone. Briefly, in humans, there have been four families of histones identified: H1, H2 (H2A and H2B), H3, and H4. Early studies demonstrated that HDAC1, HDAC2, HDAC4, HDAC5, and HDAC6 all lack specificity and were able to deacetylate all four core histone proteins, that is, H2A, H2B, H3, and H4 [116]. However, later experimental results indicate that there may be an issue of substrate specificity and preference by HDACs when it comes to deacetylating histones, although this is yet to be fully established [117,118]. For instance, HDAC6 has now been found to have no in vivo activity against histones by way of nuclear deacetylation [119], while HDACs 4, 5, and 7 all show low activity in their catalytic domains [120]. Similarly, non-histone substrates of HDACs are also the subject of intense study. To date, a comprehensive list of non-histone substrates for each HDAC and their specific functional consequences have not been fully characterized although several studies have identified some non-histone substrates for a few HDACs [115,121–123]. Among these non-histone substrates identified are transcription factors, hormone receptors, signal transducers, chaperone proteins, and proteins of the cytoskeleton network.
Epigenetic modulation: Research progress on histone acetylation levels in major depressive disorders
Published in Journal of Drug Targeting, 2023
Yuan Meng, Juan Du, Ning Liu, Yuanyuan Qiang, Lifei Xiao, Xiaobing Lan, Lin Ma, Jiamei Yang, Jianqiang Yu, Guangyuan Lu
Many class I HDACs selective inhibitors and HDACs broad-spectrum inhibitors have been identified and are currently used in anti-tumour research because of their growth-inhibiting effect [53]. The functional importance of abnormally overexpressed HDACs varies substantially depending on the specific subtype. Class I HDACs generally promote cell proliferation; furthermore, both HDAC1 and HDAC2 inhibit apoptosis in cancer cells. HDAC4, 6, 9, and 10 are closely linked to cancer angiogenesis, and class IIb HDACs HDAC6 and 10, together with HDAC3, 4, 5, and 8, hinder differentiation. Thus, HDACis targeting proliferation, differentiation, angiogenesis, and migration can be developed as potential cancer therapeutic strategies. To date, four HDACis have been approved by the US Food and Drug Administration and several others are in clinical trials [54], including suberoylanilide hydroxamic acid (SAHA) and specific HDACis (Table 2). Due to the complex relationship between HDACs and various diseases, these broad-spectrum HDACis act on many targets and are potentially toxic, with some reportedly presenting certain neurotoxicity and cardiotoxicity. Conversely, selective inhibitors have relatively safe and broad therapeutic prospects, and the discovery of selective HDACis with fewer side effects is a current research focus.
Histone deacetylase 1, Sirtuin 1, and Sirtuin 3 single-nucleotide polymorphisms and the risk of endometriosis in South Indian women
Published in Journal of Obstetrics and Gynaecology, 2022
K. V. Veena, Swapna Siddamalla, Mamata Deenadayal, Shivaji Sisinthy, Manjula Bhanoori
Our studies have demonstrated an association of the polymorphism rs1741981 (T/C) with endometriosis, which is located at the 3′ untranslated region of HDAC1. The rs1741981T/C polymorphism showed significant difference in genotype and allelic frequency between patients and controls. The frequencies of allele ‘C’ and genotype ‘CC’ was significantly higher in cases compared with controls. Variants at UTR region play essential roles in mRNA stability and post-transcriptional processes (Siddamalla et al. 2018). SNPs of HDAC1 are important indicators of genetic susceptibility to various diseases including cancer (Yang et al. 2010; Kim et al. 2013). As shown in Figure S1, the rs1741981T/C variation creates a binding site for transcription factors Sp1, GR and PR. Transcription factor Specificity protein 1 (Sp1) plays a role in promoting oncogenes required for tumour survival, metastasis, and progression (Tang et al. 2017). Glucocorticoid receptor (GR) is a ligand-activated transcription factor, via cortisol signalling it enhances cell survival in endometriosis (Monsivais et al. 2012).