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Targeting histone deacetylases for the treatment of disease.

Lawless MW, Norris S, O'Byrne KJ, Gray SG - J. Cell. Mol. Med. (2008)

Bottom Line: One modification, which has received significant attention, is that of histone acetylation.Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target.The present review will discuss the current knowledge surrounding the clinical potential and current development of histone deacetylases for the treatment of diseases for which a pro-inflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the pro-inflammatory environment.

View Article: PubMed Central - PubMed

Affiliation: Centre for Liver Disease, School of Medicine and Medical Science, Mater Misericordiae University Hospital - University College Dublin, Dublin, Ireland.

ABSTRACT
The 'histone code' is a well-established hypothesis describing the idea that specific patterns of post-translational modifications to histones act like a molecular 'code' recognized and used by non-histone proteins to regulate specific chromatin functions. One modification, which has received significant attention, is that of histone acetylation. The enzymes that regulate this modification are described as lysine acetyltransferases or KATs, and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. The pro-inflammatory environment is increasingly being recognized as a critical element for both degenerative diseases and cancer. The present review will discuss the current knowledge surrounding the clinical potential and current development of histone deacetylases for the treatment of diseases for which a pro-inflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the pro-inflammatory environment.

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Related in: MedlinePlus

Interplay of KATs and HDACs in the regulation of NF-κB.
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fig01: Interplay of KATs and HDACs in the regulation of NF-κB.

Mentions: Histone modifying enzymes such as histone deacetylases have been identified as critical regulators of pro-inflammatory cascades. One of the best-established mechanisms identified concerns the roles of these enzymes in the regulation of nuclear factor κB (NF-κB) activation, as summarized in Fig. 1. The NF-κB-Rel family consists of five subunits, but NF-κB typically consists of a heterodimeric protein comprising a p50 and a p65 (RelA) sub-unit. Early studies identified the lysine acetyltransferases KAT3B and KAT3A as key coactivators in regulating NF-κB driven gene expression [15–17]. These interactions were found to involve the RelA/p65 subunit. Another lysine acetyltransferase KAT13A was found to also potentiate NF-κB transactivation through interactions with the other subunit p50 [18]. Following the identification of interactions between NF-κB and lysine acetyltransferases it was subsequently shown that the RelA/p65 subunit could associate with HDAC1 and HDAC2 to repress expression of NF-κB regulated genes as well as to control the induced level of expression of these genes [19].


Targeting histone deacetylases for the treatment of disease.

Lawless MW, Norris S, O'Byrne KJ, Gray SG - J. Cell. Mol. Med. (2008)

Interplay of KATs and HDACs in the regulation of NF-κB.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3823402&req=5

fig01: Interplay of KATs and HDACs in the regulation of NF-κB.
Mentions: Histone modifying enzymes such as histone deacetylases have been identified as critical regulators of pro-inflammatory cascades. One of the best-established mechanisms identified concerns the roles of these enzymes in the regulation of nuclear factor κB (NF-κB) activation, as summarized in Fig. 1. The NF-κB-Rel family consists of five subunits, but NF-κB typically consists of a heterodimeric protein comprising a p50 and a p65 (RelA) sub-unit. Early studies identified the lysine acetyltransferases KAT3B and KAT3A as key coactivators in regulating NF-κB driven gene expression [15–17]. These interactions were found to involve the RelA/p65 subunit. Another lysine acetyltransferase KAT13A was found to also potentiate NF-κB transactivation through interactions with the other subunit p50 [18]. Following the identification of interactions between NF-κB and lysine acetyltransferases it was subsequently shown that the RelA/p65 subunit could associate with HDAC1 and HDAC2 to repress expression of NF-κB regulated genes as well as to control the induced level of expression of these genes [19].

Bottom Line: One modification, which has received significant attention, is that of histone acetylation.Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target.The present review will discuss the current knowledge surrounding the clinical potential and current development of histone deacetylases for the treatment of diseases for which a pro-inflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the pro-inflammatory environment.

View Article: PubMed Central - PubMed

Affiliation: Centre for Liver Disease, School of Medicine and Medical Science, Mater Misericordiae University Hospital - University College Dublin, Dublin, Ireland.

ABSTRACT
The 'histone code' is a well-established hypothesis describing the idea that specific patterns of post-translational modifications to histones act like a molecular 'code' recognized and used by non-histone proteins to regulate specific chromatin functions. One modification, which has received significant attention, is that of histone acetylation. The enzymes that regulate this modification are described as lysine acetyltransferases or KATs, and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. The pro-inflammatory environment is increasingly being recognized as a critical element for both degenerative diseases and cancer. The present review will discuss the current knowledge surrounding the clinical potential and current development of histone deacetylases for the treatment of diseases for which a pro-inflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the pro-inflammatory environment.

Show MeSH
Related in: MedlinePlus