Class IIa histone deacetylases: regulating the regulators

Martin, Maud; Kettmann, Richard; Dequiedt, Samuel

doi:10.1038/sj.onc.1210613

Cited by 223 publications

(232 citation statements)

References 181 publications

(224 reference statements)

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“…Class IIa HDACs are large proteins with multiple functions including transcription factor binding and N-acetyl lysine recognition. 1,2 Of most interest to our laboratory is the role of class IIa HDAC biology in HD, in particular the beneficial effect, which has been observed following HDAC4 genetic suppression. 3−5 Replication of these effects in preclinical models of HD via occupancy of the class IIa HDAC catalytic domain would provide a rationale for small molecule therapy.…”

mentioning

confidence: 99%

Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors

Luckhurst

Breccia

Stott

et al. 2015

ACS Med. Chem. Lett.

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Potent and selective class IIa HDAC tetrasubstituted cyclopropane hydroxamic acid inhibitors were identified with high oral bioavailability that exhibited good brain and muscle exposure. Compound 14 displayed suitable properties for assessment of the impact of class IIa HDAC catalytic site inhibition in preclinical disease models.KEYWORDS: Class IIa HDAC inhibitors, hydroxamic acid, CNS exposure, tetrasubstituted cyclopropane, cyclopropanation, Huntington's disease I nhibition of class IIa HDAC enzymes has been suggested as a therapeutic strategy for a number of indications, including Huntington's disease (HD) and muscular atrophy. Class IIa HDACs are large proteins with multiple functions including transcription factor binding and N-acetyl lysine recognition. 1,2 Of most interest to our laboratory is the role of class IIa HDAC biology in HD, in particular the beneficial effect, which has been observed following HDAC4 genetic suppression. 3−5 Replication of these effects in preclinical models of HD via occupancy of the class IIa HDAC catalytic domain would provide a rationale for small molecule therapy. Currently there are no marketed HDAC class IIa-selective inhibitors, whereas four pan-HDAC inhibitors, vorinostat (SAHA), romidepsin, belinostat, and panobinostat are on the market.Class IIa-selective HDAC inhibitors would represent important tools for elucidating the therapeutic potential of this protein family. We recently reported the structure-based design of trisubstituted cyclopropane class IIa-selective HDAC inhibitors as potential therapeutics in HD. 6 This improved selectivity was driven by exploiting a selectivity pocket ( Figure 1, shown with compound 13) that is not present in the class I HDAC isoforms. This pocket is formed as a consequence of a tyrosine-histidine substitution. 7 We now report the discovery of tetrasubstituted cyclopropane hydroxamic acid class IIa HDAC inhibitors, with additional substitution at C1 (Figure 1). These compounds exhibited improved pharmacokinetic profiles, and so may provide a further means for evaluating efficacy in preclinical in vivo HD disease models.

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confidence: 99%

Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors

Luckhurst

Breccia

Stott

et al. 2015

ACS Med. Chem. Lett.

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“…The class II HDACs have been divided into subclasses IIa (HDAC 4, 5, 7, and 9) and IIb (HDAC 6 and 10). HDAC 6 and 10 share duplication of the deacetylase domain and are localized in the cytoplasm (25), whereas many of the class IIa HDACs can shuttle between the nucleus and cytoplasm to regulate signaling and gene expression (26). A primary mechanism of action involves transcriptional derepression, in which the nuclear export of class IIa HDACs removes repressive activity, thus permitting inducible gene expression.…”

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confidence: 99%

Histone Deacetylase 7 Promotes Toll-like Receptor 4-dependent Proinflammatory Gene Expression in Macrophages

Shakespear

Hohenhaus

Kelly

et al. 2013

Journal of Biological Chemistry

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Background: Histone deacetylase (HDAC) inhibitors reduce LPS-induced inflammatory mediator production from macrophages, but the relevant HDAC targets are unknown. Results: A specific isoform of Hdac7 amplifies expression of LPS-inducible genes via a HIF-1␣-dependent mechanism in macrophages. Conclusion:The class IIa HDAC Hdac7 promotes inflammatory responses in macrophages. Significance: Hdac7 may be a viable target for developing new anti-inflammatory drugs.

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“…Based on structural and biochemical characteristics, the 18 human HDACs fall into four distinct classes, with members of the class II further divided into two subclasses, IIa and IIb (1). Class IIa HDACs (HDAC4, -5, -7, and -9) are regulated by phosphorylation-dependent nuclear export.…”

mentioning

confidence: 99%

“…Class IIa HDACs act as transcriptional modulators of specific genetic programs associated with several important developmental processes (1). In humans, HDAC7 is transiently and predominantly expressed in CD4/CD8 double positive thymocytes, where it represses the expression of nur77, a proapoptotic gene involved in negative selection (2).…”

mentioning

confidence: 99%

Protein phosphatase 2A controls the activity of histone deacetylase 7 during T cell apoptosis and angiogenesis

Martin

Potente²,

Janssens³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Class IIa histone deacetylases (HDACs) act as key transcriptional regulators in several important developmental programs. Their activities are controlled via phosphorylation-dependent nucleocytoplasmic shuttling. Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. Although a lot of effort has been made toward the identification of the inactivating kinases that phosphorylate class IIa HDAC 14-3-3 motifs, the existence of an antagonistic protein phosphatase remains elusive. Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs. Interestingly, dephosphorylation of class IIa HDACs by PP2A is prevented by competitive association of 14-3-3 proteins. Using both okadaic acid treatment and RNA interference, we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. This study unravels a dynamic interplay among 14-3-3s, protein kinases, and PP2A and provides a model for the regulation of class IIa HDACs.chromatin ͉ shuttling ͉ endothelial cells ͉ thymocytes ͉ 14-3-3 D eacetylation of histones by histone deacetylases (HDACs) results in a compact chromatin structure that imposes specific restrictions on the transcriptional machinery. Based on structural and biochemical characteristics, the 18 human HDACs fall into four distinct classes, with members of the class II further divided into two subclasses, IIa and IIb (1). Class IIa HDACs (HDAC4, -5, -7, and -9) are regulated by phosphorylation-dependent nuclear export. Several canonical binding motifs for 14-3-3 proteins are found in the N-terminal adapter domain of all class IIa HDAC members. When phosphorylated on specific serine residues, these consensus motifs recruit 14-3-3 proteins. Association with 14-3-3 overcomes the repressor activity of class IIa HDACs by eliciting their sequestration in the cytoplasm and making them unavailable for their cognate transcription factors and corepressors.Class IIa HDACs act as transcriptional modulators of specific genetic programs associated with several important developmental processes (1). In humans, HDAC7 is transiently and predominantly expressed in CD4/CD8 double positive thymocytes, where it represses the expression of nur77, a proapoptotic gene involved in negative selection (2). Recently, in situ hybridization unraveled expression of HDAC7 in the vascular endothelium of the developing mouse embryo. Consistent with this, inactivation of the HDAC7 gene led to embryonic lethality resulting from blood vessel dilatations, rupture, and hemorrhages. The vascular defects associated with HDAC7 deficiency were attributed to the up-regulation of matrix metalloproteinase 10 (MMP-10), a secreted proteinase that degrades the extracellular matrix (3).Modulation of class IIa HDAC subcellular distribution by phosphory...

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Class IIa histone deacetylases: regulating the regulators

Cited by 223 publications

References 181 publications

Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors

Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors

Histone Deacetylase 7 Promotes Toll-like Receptor 4-dependent Proinflammatory Gene Expression in Macrophages

Protein phosphatase 2A controls the activity of histone deacetylase 7 during T cell apoptosis and angiogenesis

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