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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
Class IIb HDACs consisting of HDAC6 and HDAC10 are generally present in the cytoplasm and harbor a long tail domain at the C-terminus (Seto and Yoshida, 2014). HDAC6 contains two deacetylase domains and a C-terminal zinc finger ubiquitin-binding domain, whereas HDAC10 has only one deacetylase domain and a leucine-rich repeat at C-terminus (Zhang et al., 2006). Studies have shown that HDAC6 deacetylates α-tubulin, cortactin, chaperones and IFNαR, thereby regulating autophagy (Ran et al., 2015).
Precision medicine for colorectal cancer
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Candan Hızel, Şükrü Tüzmen, Arsalan Amirfallah, Gizem Çalıbaşı Koçal, Duygu Abbasoğlu, Haluk Onat, Yeşim Yıldırım, Yasemin Baskın
The acetylation reactions of lysine amino acids on histone tails are reversible modifications and serve as activators or repressors of transcription function. For example, hypoacetylation silences gene expression, whereas hyperacetylation permits active gene transcription due to the destabilization of chromatin fibers and increasing the mobility of nucleosomes (Das and Tyler, 2013). These acetylation reactions are carried out by removing acetyl groups from lysine amino acids by histone acetyltransferases (HATs) and histone deacetylases (HDACs), as coactivators and corepressors of transcription. The balance between HATs and HDACs controls the transcriptional inhibition of tumor suppressor genes. The opposite of acetylation associates with transcriptional repression of genes (Bardhan and Liu, 2013). HDACs play a crucial role in CRC development. Up to now, 18 HDACs have been identified as corepressor multiprotein complexes and they are divided into four classes: Class I (HDAC1, HDAC2, HDAC3, and HDAC8), Class II (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10), Class III (Sirt1, Sirt2, Sirt3, Sirt4, Sirt5, Sirt6, and Sirt7), and Class IV HDACs (only HDAC11). Classes I, II, and IV HDACs have similar features due to their structure and function, but class III does not show similarity (Bolden et al., 2006). Increased expression of several HDACs has been determined in CRC. In addition, upregulation of Class I HDACs (HDAC1, HDAC2, HDAC3) has been associated with reduced patient survival in CRC (Ashktorab et al., 2009). The elevated levels of HDAC2 are accompanied with the hypoacetylation of H4K12 and H3K18 histones on the multistep carcinogenesis process of CRC (Ishihama et al., 2007). The overexpression of HDAC3 was recorded in duodenal adenomas of Apc1638N/+ mice and human colon cancers. Silencing of HDAC3 in colon cancer cell lines induced growth inhibition, and shortened survival and apoptosis (Wilson et al., 2006). Silencing of HDAC4 expression in HCT116 colorectal cancer cells resulted in growth inhibition and increased apoptosis and p21 transcription (Wilson et al., 2008).
Protein lysine acetylation and its role in different human pathologies: a proteomic approach
Published in Expert Review of Proteomics, 2021
Orlando Morales-Tarré, Ramiro Alonso-Bastida, Bolivar Arcos-Encarnación, Leonor Pérez-Martínez, Sergio Encarnación-Guevara
Class IIb is made up of only two members, HDAC6 and HDAC10. HDAC6 has been described as the more critical cytoplasmic deacetylase present in human cells. This HADC, primarily localized in the cytoplasm, is the only HDAC described so far that possesses a C-terminal zinc finger and two deacetylase domains [62]. Transmembrane proteins such as the IFNαR interferon receptor, chaperones as heat shock protein 90 (Hsp90), and cytoskeletal proteins as α-cortactin and α-tubulin (a microtubule heterodimer), have been described as proteins deacetylated by HDAC6. Consequently, several biological processes, included degradation of misfolded proteins, synapse formation, the immune response, and cell migration, are regulated by HDAC6 [63]. In contrast, slight information about HDAC10 function has been reported until now [58].
New developments in investigational HDAC inhibitors for the potential multimodal treatment of cachexia
Published in Expert Opinion on Investigational Drugs, 2019
Class I HDACs are ubiquitous and have been found in many transcriptional corepressor complexes; their activity is mainly exerted by inhibiting transcription factors, such as Sp1, p53, and the Rb protein. Class IIa and class IIb HDACs contribute to signal transduction pathways; phosphorylation causes in the former the exposure of a nuclear export sequence that allows the interaction with 14–3–3 proteins and the export to the cytoplasm. Class IIb HDAC6 and HDAC10 have been reported to deacetylate tubulin and proteins involved in autophagy [28 and refs. therein]. SIRT have been shown to contribute to biological processes, such as apoptosis, DNA repair, and autophagy, but also to play a role in the regulation of lifespan, at least in lower eukaryotes [33]. Consistently, aging, but also several chronic diseases, have been associated with altered SIRT activity [34]. HDAC11 has been discovered in 2002 and is the unique member of class IV HDACs. Its intracellular localization may vary in relation with cell type and environmental cues [35].
Zinc binding groups for histone deacetylase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Lei Zhang, Jian Zhang, Qixiao Jiang, Li Zhang, Weiguo Song
Woster and co-workers reported the 2-(oxazol-2-yl)phenol moiety as a novel ZBG that can be used for the design of potent HDACIs63. A series of 2-(oxazol-2-yl)phenol derivatives were synthesised and tested in the activity assay. The derived molecules exhibited potent HDAC1, HDAC6 and HDAC10 inhibitory activities. Among these compounds, molecule 20 (IC50 7.5 μM against MV-4–11 leukemia cell line) could efficiently induce the acetylation of histone 3 lysine 9 (H3K9) and p21Waf1/CIP1 compared with SAHA. Molecular modelling analysis revealed that 2-(oxazol-2-yl)phenol group shows a similar zinc-binding pattern as the benzamide group in the ligand of a crystal structure (PDB entry: 4LY1). Although no remarkable selectivity was observed, the 2-(oxazol-2-yl)phenol derivatives are considered promising candidates as ZBG in the development of novel and potent HDAC inhibitory drugs.