Histone deacetylases and the immunological network: implications in cancer and inflammation

Villagra, Alejandro; Sotomayor, Eduardo M.; Seto, Edward

doi:10.1038/onc.2009.334

Cited by 169 publications

(114 citation statements)

References 176 publications

(164 reference statements)

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“…The increase in histone acetylation is associated with decreased histone deacetylase (HDAC) activity. For example, promoters of several pro-inflammatory cytokines (IL-1, IL-2, IL-8, and IL-12) are rapidly acetylated by CBP/p300, leading to transcriptional activation, and display reduced HDAC activity (Villagra et al, 2010). The recruitment of HDACs, in contrast, leads to histone deacetylation and gene repression.…”

Section: Histone Acetylation and Inflammationmentioning

confidence: 99%

“…The recruitment of HDACs, in contrast, leads to histone deacetylation and gene repression. HDACs regulate transcription of both pro-and anti-inflammatory cytokines through their recruitment to gene promoters via corepressor complexes and transcription factors such as FOXP3, STATs, GATAs, ZEB1, and NF-κB (Villagra et al, 2010).…”

Section: Histone Acetylation and Inflammationmentioning

confidence: 99%

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Epigenetic Mechanisms in Inflammation

2010

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Epigenetic modifications occur in response to environmental changes and play a fundamental role in gene expression following environmental stimuli. Major epigenetic events include methylation and acetylation of histones and regulatory factors, DNA methylation, and small non-coding RNAs. Diet, pollution, infections, and other environmental factors have profound effects on epigenetic modifications and trigger susceptibility to diseases. Despite a growing body of literature addressing the role of the environment on gene expression, very little is known about the epigenetic pathways involved in the modulation of inflammatory and anti-inflammatory genes. This review summarizes the current knowledge about epigenetic control mechanisms during the inflammatory response.

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Section: Histone Acetylation and Inflammationmentioning

confidence: 99%

Section: Histone Acetylation and Inflammationmentioning

confidence: 99%

Epigenetic Mechanisms in Inflammation

2010

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“…Acetylation of histones represents one of several epigenetic modifications (9,10). Altering gene expression through chromatin modifications induced by acetylation and deacetylation of histone tails has gained wide attention (11). Histone deacetylase inhibitors (HDACi) cause reversible inhibition of HDAC enzymes, remodel chromatin, regulate gene expression (12) and have shown efficacy in vitro and in vivo as antitumor agents (13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

HDAC Inhibition and Graft Versus Host Disease

Choi

Reddy

2011

Mol Med

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Histone deacetylase (HDAC) inhibitors are currently used clinically as anticancer drugs. Recent data have demonstrated that some of these drugs have potent antiinflammatory or immunomodulatory effects at noncytotoxic doses. The immunomodulatory effects have shown potential for therapeutic benefit after allogeneic bone marrow transplantation in several experimental models of graft versus host disease (GVHD). These effects, at least in part, result from the ability of HDAC inhibitors (HDACi) to suppress the function of host antigen presenting cells such as dendritic cells (DC). HDACi reduce the dendritic cell (DC) responses, in part, by enhancing the expression of indoleamine 2,3-dioxygenase (IDO) in a signal transducer and activator of transcription-3 (STAT-3) dependent manner. They also alter the function of other immune cells such as T regulatory cells and natural killer (NK) cells, which also play important roles in the biology of GVHD. Based on these observations, a clinical trial has been launched to evaluate the impact of HDAC inhibitors on clinical GVHD. The experimental, mechanistic studies along with the brief preliminary observations from the ongoing clinical trial are discussed in this review.

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“…2 HDACs are involved in deacetylation of histones and nonhistone proteins, including transcription factors, structural proteins, and enzymes, and have an important role in chromatin structure, gene regulation, and control of cell metabolism and cancer (1)(2)(3). Because of the vast list of the cellular roles of HDACs, it is imperative that the mechanisms that regulate these enzymes are completely understood.…”

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confidence: 99%

HDAC3 Is Negatively Regulated by the Nuclear Protein DBC1

Chini

Escande

Nin

et al. 2010

Journal of Biological Chemistry

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HDAC3 is a member of the class I histone deacetylase family that regulates gene expression by deacetylation of histones and non-histone proteins. HDAC3 activity has been shown to be modulated by interaction with the co-repressors NCoR and SMRT. Here, we present evidence that the nuclear protein DBC1 is an endogenous inhibitor of HDAC3. DBC1 has been previously identified as a regulator of some nuclear receptors, the methyltransferase SUV39H1, and the NAD-dependent deacetylase SIRT1. Furthermore, DBC1 has been shown to influence transcription regulation and apoptosis, and it may also act as a tumor suppressor. We found that DBC1 interacts and specifically inhibits the deacetylase HDAC3. This interaction depends on the N terminus of DBC1 and the C terminus of HDAC3. Expression of DBC1 not only inhibited HDAC3 activity but also altered its subcellular distribution. In addition, knockdown of endogenous DBC1 in cells and knock-out in mouse tissues increased HDAC3 deacetylase activity. Together, these results identify DBC1 as a new regulator of HDAC3 and demonstrate that DBC1 is a negative regulator of two key distinct deacetylases, SIRT1 and HDAC3. These findings may lead to a better understanding of the biological roles of DBC1 and HDAC3 in metabolic diseases and cancer.Levels of acetylation in cells are maintained by the complementary activities of two families of enzymes, the histone acetyltransferases and the histone deacetylases (HDACs). 2HDACs are involved in deacetylation of histones and nonhistone proteins, including transcription factors, structural proteins, and enzymes, and have an important role in chromatin structure, gene regulation, and control of cell metabolism and cancer (1-3). Because of the vast list of the cellular roles of HDACs, it is imperative that the mechanisms that regulate these enzymes are completely understood. The HDAC superfamily is vast, and these proteins can be classified into four classes, class I, II, III (sirtuins), and IV, based on their homology. Class I includes HDAC1-HDAC3, and HDAC8; class II includes HDAC4 -HDAC7, HDAC9, and HDAC10; class III consists of members of the sirtuin family of HDACs; and class IV is represented by HDAC11. In the sirtuin family of deacetylases, special attention has been given to SIRT1 due to its important role in stress responses, cell metabolism, and possibly aging and longevity (4, 5). Understanding the regulation of deacetylases has been the focus of intense investigation. However, the precise mechanisms that regulate HDACs have not been defined.We and others have recently described that SIRT1 deacetylase is regulated by interaction with the nuclear protein (DBC1 (deleted in breast cancer-1) (6 -8). DBC1 was initially described as being absent in certain human breast cancers and has been recently shown to bind and regulate SIRT1, nuclear receptors (such as the estrogen and androgen receptors), and the methyltransferase SUV39H1 (9 -11). Furthermore, DBC1 has been implicated as a key component of the molecular mechanism of cellular apoptosis and...

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Histone deacetylases and the immunological network: implications in cancer and inflammation

Cited by 169 publications

References 176 publications

Epigenetic Mechanisms in Inflammation

Epigenetic Mechanisms in Inflammation

HDAC Inhibition and Graft Versus Host Disease

HDAC3 Is Negatively Regulated by the Nuclear Protein DBC1

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