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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
HDAC3’s phospho-acceptor site, S424, which is a non-conserved residue among the Class I HDACs, when mutated to alanine severely compromises enzymatic activity of HDAC1 and HDAC2. Unlike HDAC1 and HDAC2, the HDAC3 associates with the catalytic and regulatory subunits of the protein serine/threonine phosphatase 4 complex (PP4c/PP4R1), and dephosphorylation of HDAC3 by PP4 down-regulates HDAC3 enzymatic activity (Zhang et al., 2005). Phosphorylation of HDAC8 at S39 leads to the disruption in the surface structure, which ultimately leads to the negative effect of HDAC8. Phosphorylation of Class IIa HDACs may lead to their ubiquitination and proteasomal degradation. Two phosphatases have been implicated in the regulation of Class IIa HDACs activities and functions: protein phosphatase 1b (PP1b), including myosin phosphatase targeting subunit 1 (MYPT1, a regulatory subunit of PP1), and protein phosphatase 2A (PP2A). Class IIb HDACs, global proteomic profiling of phosphopeptides, revealed that HDAC6 is phosphorylated at S22 and T30 (Beausoleil et al., 2004).
Peripheral muscles
Published in Claudio F. Donner, Nicolino Ambrosino, Roger S. Goldstein, Pulmonary Rehabilitation, 2020
Luis Puente-Maestu, François Maltais, André Nyberg, Didier Saey
A 28% decrease in the glucose transporters GLUT1, GLUT4 has been reported in the quadriceps of COPD patients (27); this may be another feature of type I fibre atrophy, since type IIx fibres are phenotypically less sensitive to insulin (28). Recently, the expression of the histone deacetylases HDAC3, HDAC4 and sirtuin-1 have been found reduced in COPD with muscle depletion (7). These changes may also be associated with reduced glucose utilization and reciprocally enhanced lipid oxidation, a metabolic modification that typically leads to reduced muscle force and may increase resistance to insulin (29).
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).
Phosphorus containing analogues of SAHA as inhibitors of HDACs
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Michael D. Pun, Hsin-Hua Wu, Feyisola P. Olatunji, Britany N. Kesic, John W. Peters, Clifford E. Berkman
Our inhibitor selectivity experiments focussed on the Class-I HDACs (HDAC1, 2, 3, and 8). The HDAC isoforms 3 and 8 were chosen from this class due to the differences in their sequence and structure. Both of these enzymes are present in the cell nucleus and use zinc as a cofactor for catalytic activity. There are 4 key differences in the active site amino acid sequence suggesting that there is a selectivity towards substrates24. HDAC8 contains a flexible L1 loop made up of 7 amino acids that form a hydrophobic secondary pocket adjacent to the active site25. This pocket has been exploited for HDAC8-specific inhibitor research and has led to “L shaped” molecules with improved activity against HDAC826. These HDACs are clinically relevant due to HDAC 8 being overexpressed in T-Cell leukaemia and Neuroblastoma27,28. HDAC3, however, is associated with neurodegenerative diseases such as Alzheimer’s disease.
Upregulation of OATP1A2 in human oesophageal squamous cell carcinoma cells via the HDAC6-GCN5/PCAF-H3K9Ac axis
Published in Xenobiotica, 2021
Xiaoli Zheng, Jian V. Zhang, Yanfeng Bai, Jiaqi Wang, Mingfeng Jiang, Su Zeng, Lvhua Wang
Histone deacetylation is performed by histone acetylation ‘erasers’ (HDACs), which are involved in a variety of malignancies. HDACs are often dysregulated in human tumours. For example, overexpression of HDAC3 has been observed in various cancers (ovarian and lung cancers, colon cancer, and chronic lymphocyte leukemia) and is associated with poor outcomes (Weichert et al. 2008; Thangaraju et al. 2009; Hayashi et al. 2010; Tanimoto et al. 2017; Ferrante et al. 2020). Although HDACs levels are usually increased during tumour development, it has been noted that inactivation of HDACs might also demonstrate tumorigenic effects. HDAC6 repression promotes angiogenesis and predicts poor survival in hepatocellular carcinoma (Yang et al. 2019). In this study, we observed that HDAC6 mRNA levels from GEPIA data were downregulated in ESCC tissues, indicating that the regulation of the OATP1A2 promoter region enhanced its expression in ESCC. ChIP assays were performed to demonstrate that the upregulation of OATP1A2 transcription was mediated by H3K9Ac. We further attempted to discover potential factors of HATs that regulate the H3K9Ac status and observed that histone acetylase GCN5/PCAF might enrich H3K9Ac in the OATP1A2 promoter region. Collectively, these data suggest that OATP1A2 might have tumorigenic effects mediated by HDAC6-GCN5/PCAF-H3K9Ac axis and may be a potential therapeutic target in ESCC.
Cross-talk between energy metabolism and epigenetics during temperature stress response in C2C12 myoblasts
Published in International Journal of Hyperthermia, 2019
Basavaraj Sajjanar, Puntita Siengdee, Nares Trakooljul, Xuan Liu, Claudia Kalbe, Klaus Wimmers, Siriluck Ponsuksili
Histone acetyl transferases (HATs), responsible for acetylation of histone tails, include the three major subtypes p300, Gcn5 and Cbp. The overall expression levels of HATs were increased in response to rising temperatures. Noteworthy, the Gcn5 subtype was significantly upregulated in high thermal stress (41 °C) and downregulated by low temperature stress (35 °C), compared to normothermic condition (Figure 8). Histone deacetylases (HDACs) are responsible for removal of acetyl group from the tails of histones belonging to class I HDACs (Hdac1, Hdac2, Hdac3 and Hdac8) and class II HDACs (Hdac4, Hdac5, Hdac6, Hdac7 and Hdac9). Under low-temperature conditions (35 °C), Hdac2 and Hdac8 (Class I) as well as Hdac4 and Hdac5 (Class II), were significantly downregulated relative to the control cells, while Hdac6 and Hdac7 tended to be upregulated, albeit the latter changes did not reach statistical significance. Hdac8 (Class I) and Hdac7 (Class II) were significantly downregulated in both high-temperature conditions tested (39 °C and 41 °C) (Figure 9). In contrast, Hdac9 was upregulated in the high temperature conditions.