Article

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

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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Available from: Xiang-Jiao Yang, Oct 20, 2015
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    • "Zinc - dependent class I , II and IV HDACs as well as the NAD - dependent class III HDACs , the sirtuins , antagonize the activity of HATs . Similarly to the HATs , HDAC proteins show a low level of specificity that is mainly regulated by the interaction with other non - catalytic proteins and complexes ( Yang and Seto , 2007 ) . "
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    ABSTRACT: Alzheimer's disease (AD) is the major cause of dementia in Western societies. It progresses asymptomatically during decades before being belatedly diagnosed when therapeutic strategies have become unviable. Although several genetic alterations have been associated with AD, the vast majority of AD cases do not show strong genetic underpinnings and are thus considered a consequence of non-genetic factors. Epigenetic mechanisms allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and recently, a growing number of epigenetic alterations in AD have been described. For instance, an accumulation of dysregulated epigenetic mechanisms in aging, the predominant risk factor of AD, might facilitate the onset of the disease. Likewise, mutations in several enzymes of the epigenetic machinery have been associated with neurodegenerative processes that are altered in AD such as impaired learning and memory formation. Genome-wide and locus-specific epigenetic alterations have also been reported, and several epigenetically dysregulated genes validated by independent groups. From these studies, a picture emerges of AD as being associated with DNA hypermethylation and histone deacetylation, suggesting a general repressed chromatin state and epigenetically reduced plasticity in AD. Here we review these recent findings and discuss several technical and methodological considerations that are imperative for their correct interpretation. We also pay particular focus on potential implementations and theoretical frameworks that we expect will help to better direct future studies aimed to unravel the epigenetic participation in AD.
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    • "HDIs should not be considered to act only on HDACs but also act onnonhistone transcription factors and transcriptional co-regulators. HDIs can alter the degree of acetylation nonhistone effector molecules and, therefore, increase or repress the transcription of genes by this mechanism [9] "

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    • "Acetylation and deacetylation are posttranslational protein modifications that regulate many cellular processes, such as chromatin assembly and gene transcription (Quivy and Van Lint, 2004; Yang and Seto, 2007). The competition between two groups of enzymes—histone acetyltransferases and histone deacetylases (HDACs)—determines the histone-acetylation state (Yang and Seto, 2007). HDACs remove acetyl groups from specific lysine residues on histone proteins to regulate chromatin architecture and gene expression . "
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    ABSTRACT: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy, because it can induce apoptosis in various tumor cells but not in most normal cells. Although it is well known that TRAIL and its receptors are expressed in many types of normal cells, including immune cells, their immunological effects and regulatory mechanisms are still obscure. In the present study, we demonstrated that TRAIL affected the activity of NF-κB (nuclear factor-κB) and the expression of its downstream proinflammatory cytokines IL-1β (interleukin-1β), IL-6, and tumor necrosis factor α in macrophages. TRAIL also induced microRNA-146a (miR-146a) expression in an NF-κB-dependent manner. As a result, miR-146a was involved as a negative-feedback regulator in the down-regulation of proinflammatory cytokine expression. In addition, the suppression of histone deacetylase (HDAC) activities by trichostatin A improved miR-146a expression due to the up-regulation of the DNA-binding activity of NF-κB at the miR-146a promoter in TRAIL-induced macrophages, suggesting that histone acetylation was involved in the suppression of miR-146a expression. Further investigation revealed that the HDAC subtype HDAC1 directly regulated the expression of miR-146a in TRAIL-stimulated macrophages. Finally, the TRAIL-sensitive human non small cell lung carcinoma cell line NCI-H460 was used to elucidate the physiological significance of TRAIL with respect to tumor-associated macrophages (TAMs). We demonstrated that TRAIL re-educated TAMs to an M1-like phenotype and induced cytotoxic effects in the tumor cells. These data provide new evidence for TRAIL in the immune regulation of macrophages and may shed light on TRAIL-based antitumor therapy in human patients.
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