HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention

Molecular Oncology Group, Department of Medicine, McGill University Health Center, Montréal, Québec, Canada.
Oncogene (Impact Factor: 8.56). 09/2007; 26(37):5310-8. DOI: 10.1038/sj.onc.1210599
Source: PubMed

ABSTRACT 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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    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 · 6.82 Impact Factor
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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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    ABSTRACT: Histone acetylation is essential for hippocampal memory formation in young adult rodents. Although dysfunctional histone acetylation has been associated with age-related memory decline in male rodents, little is known about whether histone acetylation is altered by aging in female rodents. In young female mice, the ability of 17β-estradiol (E2) to enhance object recognition memory consolidation requires histone H3 acetylation in the dorsal hippocampus. However, the extent to which histone acetylation is regulated by E2 in middle-aged females is unknown. The mnemonic benefits of E2 in aging females appear to be greatest in middle age, and so pinpointing the molecular mechanisms through which E2 enhances memory at this age could lead to the development of safer and more effective treatments for maintaining memory function without the side effects of current therapies. Here, we show that dorsal hippocampal infusion of E2 rapidly enhanced object recognition and spatial memory, and increased histone H3 acetylation in the dorsal hippocampus, while also significantly reducing levels of histone deacetylase (HDAC2 and HDAC3) proteins. E2 specifically increased histone H3 acetylation at Bdnf promoters pII and pIV in the dorsal hippocampus of both young and middle-aged mice, despite age-related decreases in pI and pIV acetylation. Furthermore, levels of mature BDNF and pro-BDNF proteins in the dorsal hippocampus were increased by E2 in middle-aged females. Together, these data suggest that the middle-aged female dorsal hippocampus remains epigenetically responsive to E2, and that E2 may enhance memory in middle-aged females via epigenetic regulation of Bdnf.
    Learning & memory (Cold Spring Harbor, N.Y.) 09/2014; 21(9):457-67. DOI:10.1101/lm.034033.113 · 4.38 Impact Factor


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