Yang XJ, Seto E.. HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 26: 5310-5318

Molecular Oncology Group, Department of Medicine, McGill University Health Center, Montréal, Québec, Canada.
Oncogene (Impact Factor: 8.46). 09/2007; 26(37):5310-8. DOI: 10.1038/sj.onc.1210599
Source: PubMed


Acetylation of the epsilon-amino group of a lysine residue was first discovered with histones in 1968, but the responsible enzymes, histone acetyltransferases and deacetylases, were not identified until the mid-1990s. In the past decade, knowledge about this modification has exploded, with targets rapidly expanding from histones to transcription factors and other nuclear proteins, and then to cytoskeleton, metabolic enzymes, and signaling regulators in the cytoplasm. Thus, protein lysine acetylation has emerged as a major post-translational modification to rival phosphorylation. In this issue of Oncogene, 19 articles review various aspects of the enzymes governing lysine acetylation, especially about their intimate links to cancer. To introduce the articles, we highlight here four central themes: (i) multisubunit enzymatic complexes; (ii) non-histone substrates in diverse cellular processes; (iii) interplay of lysine acetylation with other regulatory mechanisms, such as noncoding RNA-mediated gene silencing and activation; and (iv) novel therapeutic strategies and preventive measures to combat cancer and other human diseases.

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Available from: Xiang-Jiao Yang, Oct 20, 2015
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    • "Another group of compounds, the histone deacetylase (HDAC) inhibitors, including trichostatin A (TSA), SAHA (vorinostat), sodium butyrate and LAQ824, were also reported to induce proteasomal degradation of HIF-1α in a VHL-independent manner similar to Hsp90 inhibitors [Fath et al., 2006; Qian et al., 2006] (Table 1. Those HDACIs with suppressive effect on HIF-1 usually non-selectively inhibit all Class I and Class II HDACs, including HDAC1–9 [Chen and Sang, 2011; Yang and Seto, 2007]. Recently, a member of Class IIa HDACs, HDAC5, has been identified as the specific HDAC member that facilitates the stabilization and nuclear accumulation of HIF-1α protein [Chen et al., 2015]. "
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    ABSTRACT: HIF-1 activation has been well known as an adaptive strategy to hypoxia. Recently it became clear that hypoxia was often accompanied by insufficient supply of glucose or amino acids as a common result of poor circulation that frequently occurs in solid tumors and ischemic lesions, creating a mixed nutrient insufficiency. In response to nutrient insufficiency, stressed cells elicit survival strategies including activation of AMPK and HIF-1 to cope with the stress. Particularly, in solid tumors, HIF-1 promotes cell survival and migration, stimulates angiogenesis, and induces resistance to radiation and chemotherapy. Interestingly, radiation and some chemotherapeutics are reported to trigger the activation of AMPK. Here we discuss the recent advances that may potentially link the stress responsive mechanisms including AMPK activation, ATF4 activation and the enhancement of Hsp70/Hsp90 function to HIF-1 activation. Potential implication and application of the stress-facilitated HIF-1 activation in solid tumors and ischemic disorders will be discussed. A better understanding of HIF-1 activation in cells exposed to stresses is expected to facilitate the design of therapeutic approaches that specifically modulate cell survival strategy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Biochemistry 07/2015; DOI:10.1002/jcb.25283 · 3.26 Impact Factor
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    • "In general, hypoacetylated histones are associated with gene repression, whereas hyperacetylated histones are related to gene activation. HDACs in all eukaryotes may be grouped into three families: RPD3/HDA1 (Reduced Potassium Dependence 3/His- tone Deacetylase 1), SIR2 (Silent Information Regulator 2) and HD2 (Histone Deacetylase 2) (Yang and Seto, 2007; Liu et al., 2014). The Arabidopsis RPD3/HDA1 family HDACs may be further divided into three classes. "
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    ABSTRACT: The acetylation level of histones on lysine residues regulated by histone acetyltransferases and histone deacetylases plays an important yet understudied role in the control of gene expression in plants. With the aim of characterizing the Arabidopsis RPD3/HDA1 family histone deacetylase HDA5, we here present evidence indicating that HDA5 displays deacetylase activity. Mutants defective in the expression of HDA5 displayed a late flowering phenotype. The expression of the flowering repressors, FLC and MAF1, was up-regulated in hda5 mutants. Furthermore, the gene activation markers, histone H3 acetylation and H3K4 trimethylation at FLC and MAF1 chromatin were increased in hda5-1 mutants. Chromatin immuneprecipitation analysis showed that HDA5 binds to the chromatin of FLC and MAF1. Bimolecular fluorescence complementation assays and co-immunoprecipitation assays revealed that HDA5 interacts with FVE, FLD and HDA6, indicating that these proteins are in the same protein complex involved in the regulation of flowering time. Comparing gene expression profiles of hda5 and hda6 mutants by RNA-seq revealed that HDA5 and HDA6 co-regulate gene expression in multiple development processes and pathways. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    The Plant Journal 04/2015; 82(6). DOI:10.1111/tpj.12868 · 5.97 Impact Factor
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    • "Acetylation of histones is one of the crucial parts of the epigenetic transcriptional regulation. Histone acetyltransferase (Hat) and histone deacetylase (Hdac) control the balance of histone acetylation (Yang and Seto 2007). "
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    ABSTRACT: Propolis is a resinous product produced by honey bees and is known to have antitumor functions. On the other hand, histone deacetylase (Hdac) inhibitors have recently attracted attention for their antitumor effects. In this study, we examined whether Brazilian green propolis has an Hdac inhibitory activity and its contribution on antitumor effects. By in vitro Hdac activity assay, Brazilian propolis extract (BPE) significantly inhibited the enzyme activity. Actually, BPE treatment increased the intracellular histone acetylation in Neuro2a cells. Regarding antitumor effect in Neuro2a cells, BPE treatment significantly decreased cell viability. An Hdac activator theophylline significantly attenuated the effect. Then, we analyzed whether the decreasing effect on cell number was caused by cell death or growth retardation. By live/dead cell staining, BPE treatment significantly increased the dead cell number. By cell cycle analysis, BPE treatment retarded cell cycle at the M-phase. Both of these cellular effects were suppressed by addition of theophylline. These data indicate that BPE induced both cell death and growth retardation via Hdac inhibitory activity. We demonstrated that Brazilian propolis bears regulatory functions on histone acetylation via Hdac inhibition, and the effect contributes antitumor functions. Our data suggest that intake of Brazilian propolis shows preventing effects against cancer.
    Food Science & Nutrition 09/2014; 2(5). DOI:10.1002/fsn3.131
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