Structural Snapshots of Human HDAC8 Provide Insights into the Class I Histone Deacetylases

Somoza, John R.; Skene, R.J.; Katz, B.A.; Mol, Clifford D.; Ho, Joseph; Jennings, Andy; Luong, Christine; Arvai, A.S.; Buggy, Joseph J.; Chi, Ellen; Tang, Jie; Sang, Bi‐Ching; Verner, Erik; Wynands, R.; Leahy, Ellen M.; Dougan, D.R.; Snell, G.; Navre, Marc; Knuth, Mark W.; Swanson, Ronald V.; McRee, Duncan E.; Tari, Leslie W.

doi:10.1016/j.str.2004.04.012

Cited by 646 publications

(760 citation statements)

References 37 publications

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“…On the other hand, HDAC-selective inhibitors would constitute (in addition to genetic tools) a useful experimental tool to address the issue of assigning distinct biological functions to individual HDACs. From the structure of HDAC8 or HDLP (a HDAClike protein isolated from Aquifex aeolicus), and the structure of these enzymes in complex with a small number of HDACi, a few key points have emerged about the active site that support a pharmacophore model for HDAC inhibition [76][77][78][79] (FIG. 3c).…”

Section: Inhibiting Hdacsmentioning

confidence: 99%

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

2006

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| Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols.Histone deacetylases (HDACs) have been intensively scrutinized over the past few years for two main reasons. First, they have been linked mechanistically to the pathogenesis of cancer, as well as several other diseases. Second, small-molecule HDAC inhibitors (HDACi) exist that have the capacity to interfere with HDAC activity and can therefore achieve significant biological effects in preclinical models of cancer. These findings justified the introduction of HDACi into clinical trials. These initial clinical trials have just ended and show encouraging results. At this stage it is crucial to evaluate whether our current knowledge on the mechanisms of tumorigenesis that are linked to HDACs, and on the mechanisms of tumour sensitivity to HDACi, is firm enough to improve the design of further clinical trials. Recent structural and chemical data have emerged that will help in the design of novel HDACi with more desirable properties than the existing ones. However, key areas of investigation that might help to further illuminate the design of successful HDACi-based cancer therapy remain poorly explored. Novel findings indicate that our understanding of how HDACi work will probably change significantly, establishing a new paradigm in the field of intelligent drug design with broad implications for the design of targeted therapies in cancer and possibly other diseases.HDACs: enzymes looking for substrate(s) Four HDAC classes have been identified (FIG. 1a). One of them (class 3 or the so-called sirtuins, from the yeast protein Sir2) constitutes a structurally unrelated, NADdependent subfamily, and will not be considered here; neither will the class 3-specific HDACi, which are less characterized than those for the other classes 1 .An extensive phylogenetic analysis of HDACs has been performed 2,3 . HDACs are members of an ancient enzyme family found in animals, plants, fungi and bacteria. It is thought that HDACs evolved in the absence of histone proteins. Indeed, eukaryotic HDACs can deacetylate non-histone as well as histone substrates, and some HDACs reside in the cytoplasm (where histones are synthesized and acetylated for proper assembly, without the intervention of HDACs) and in mitochondria (where histones are absent).Are HDACs, then, truly HDACs 4 ? We postulate that key HDAC substrates might not be histones, but instead belong to the growing list of acetylated non-histone proteins (FIG. 1b and Supplementary information S1 ...

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Section: Inhibiting Hdacsmentioning

confidence: 99%

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

2006

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“…More recently, the crystal structure of HDAC8/hydroxamate complex has been solved [Somoza et al, 2004]. These studies provide an understanding of the three dimensional structure of the catalytic site of HDACs and insight into the mechanism for the deacetylation of acetylated lysine substrates.…”

Section: Histone Deacetylase Inhibitorsmentioning

confidence: 99%

Prospects: Histone deacetylase inhibitors

Dokmanovic

Marks

2005

J of Cellular Biochemistry

441

363

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Histone deacetylase (HDAC), inhibitors represent a new class of targeted anti-cancer agents. Several of these compounds are in clinical trials with significant activity against a spectrum of both hematologic and solid tumors at doses that are well tolerated by the patients. The HDAC inhibitors are a structurally diverse group of molecules that can induce growth arrest, differentiation, apoptosis, and autophagocytic cell death of cancer cells. While the base sequence of DNA provides the genetic code for proteins, the expression of genes is regulated, in large part, by the structure of the chromatin proteins around which the DNA is wrapped (epigenetic gene regulation). The acetylation and deacetylation of the lysines in the tails of the core histones, among the most extensively studied aspects of chromatin structure, is controlled by the action of two families of enzymes, histone deacetylases (HDACs) and histone acetyltransferases (HATs). Protein components of transcription factor complexes and many other non-histone proteins are also substrates for HDACs and HATs. The structure and activity of these non-histone proteins may be altered by acetylation/deacetylation with consequent effects on various cell functions including gene expression, cell cycle progression, and cell death pathways. This review focuses on several key questions with respect to the mechanism of action of HDACi, including, what are the different cell phenotypes induced by HDACi, why are normal cells compared to transformed cells relatively resistant to HDACi induced cell death, why are certain tumors more responsive to HDACi than others, and what is the basis of the selectivity of HDACi in altering gene expression. The answers to these questions will have therapeutic importance since we will identify targets for enhancing the efficacy and safety of HDACi.

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“…More recently, the crystal structure of HDAC8-hydroxamate interaction has been solved (Somoza et al, 2004;Vannini et al, 2004). These studies provide an insight into the mechanism of deacetylation of acetylated substrates.…”

Section: Introductionmentioning

confidence: 99%