Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin

Furumai, Ryohei; Komatsu, Yasuhiko; Nishino, Norikazu; Khochbin, Saadi; Yoshida, Minoru; Horinouchi, Sueharu

doi:10.1073/pnas.98.1.87

Cited by 354 publications

(122 citation statements)

References 47 publications

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“…It is possible that HDAC6, due to its association with HDAC11 in vivo, is contributing to the observed in vitro enzymatic activities. However, HDAC6's enzymatic activity is highly resistant to trapoxin (43), whereas the activity derived from immunoprecipitated HDAC11 is completely inhibited at 200 nM. Therefore, we conclude that HDAC11 is a bona fide histone deacetylase.…”

Section: Discussionmentioning

confidence: 81%

Cloning and Functional Characterization of HDAC11, a Novel Member of the Human Histone Deacetylase Family

Gao¹,

Cueto²,

Asselbergs³

et al. 2002

Journal of Biological Chemistry

650

497

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We have cloned and characterized a human cDNA that belongs to the histone deacetylase family, which we designate as HDAC11. The predicted HDAC11 amino acid sequence reveals an open reading frame of 347 residues with a corresponding molecular mass of 39 kDa. Sequence analyses of the putative HDAC11 protein indicate that it contains conserved residues in the catalytic core regions shared by both class I and II mammalian HDAC enzymes. Putative orthologues of HDAC11 exist in primate, mouse, Drosophila, and plant. Epitopetagged HDAC11 protein expressed in mammalian cells displays histone deacetylase activity in vitro. Furthermore, HDAC11's enzymatic activity is inhibited by trapoxin, a known histone deacetylase inhibitor. Multiple tissue Northern blot and real-time PCR experiments show that the high expression level of HDAC11 transcripts is limited to kidney, heart, brain, skeletal muscle, and testis. Epitope-tagged HDAC11 protein localizes predominantly to the cell nucleus. Co-immunoprecipitation experiments indicate that HDAC11 may be present in protein complexes that also contain HDAC6. These results indicate that HDAC11 is a novel and unique member of the histone deacetylase family and it may have distinct physiological roles from those of the known HDACs.In eukaryotes, DNA is packaged into chromatin structures, whose basic unit is the nucleosome. Each nucleosome consists of ϳ148 bp DNA wrapping around a core histone octamer, which includes two copies each of H2A, H2B, H3, and H4 (1). The packaging of DNA generally creates a repressive environment for gene expression; therefore, transcriptional activation of many genes requires chromatin modifications, such as the reversible acetylation of core histones. Transfer of an acetyl group from acetyl-CoA onto the ⑀-amino group of various lysine residues in the NH 2 -terminal tails of core histones is a ubiquitous process found in all eukaryotes examined. The steady state level of acetylation is controlled by the competing activities of histone acetyltransferases and histone deacetylases (HDACs).1 In general, hypoacetylated chromatin is associated with gene silencing, whereas hyperacetylation correlates with gene activation (2-5). However, recent studies have shown that histone deacetylation can also play a significant role in transcriptional activation. For example, inhibition of HDACs by trichostatin A or trapoxin both activates and silences a small fraction of cellular genes in mammalian cells (6, 7). Furthermore, mutation of the yeast histone deacetylases RPD3 and SIN3 shows that both genes are required to fully activate or to repress specific promoters (6, 8 -10). Finally, there is increasing evidence to support the idea that acetylation/deacetylation of non-histone proteins may also function in activation as well as repression of transcription (11)(12)(13)(14).Since the discovery of histone deacetylase RPD3 in Saccharomyces cerevisiae, numerous HDACs have been identified in mammalian cells, and are grouped into three classes based on sequence homologies. Members of...

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Section: Discussionmentioning

confidence: 81%

Cloning and Functional Characterization of HDAC11, a Novel Member of the Human Histone Deacetylase Family

Gao¹,

Cueto²,

Asselbergs³

et al. 2002

Journal of Biological Chemistry

650

497

View full text Add to dashboard Cite

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“…Histone deacetylase enzyme activities are inhibited by TSA through direct interaction of TSA with histone deacetylases (52,53). TSA increases the acetylation level and transcriptional activity in p53 (51).…”

Section: Discussionmentioning

confidence: 99%

Acetylation of Steroidogenic Factor 1 Protein Regulates Its Transcriptional Activity and Recruits the Coactivator GCN5

Jacob

Lund

Martinez

et al. 2001

Journal of Biological Chemistry

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In this study we demonstrate that SF-1 is acetylated in vivo. Histone acetyltransferase GCN5 acetylates SF-1 in vitro. Moreover, we found that SF-1 recruited a novel coactivator GCN5, which can be a newly identified coactivator for SF-1. Acetylation of SF-1 stimulates its transcriptional activity. Inhibition of deacetylation by trichostatin A, a histone deacetylase inhibitor, increased SF-1-mediated transactivation and stabilized and induced the nuclear export of the SF-1 protein.

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“…The treatment of mammalian cells with potent inhibitors of HDACs such as TSA or trapoxin was shown to result in increased expression of a variety of genes (Kijima et al, 1993;Yoshida et al, 1995). At very low concentrations, inhibitors of HDACs induce hyperacetylation of core histones, which is accompanied by characteristic blockage of the cell cycle as well as by various cellular phenotypic changes (Medina et al, 1997;Dangond and Gullans, 1998;Chen and Townes, 2000;Furumai et al, 2001). Usually, TSA is used only as an HDACs inhibitor to increase acetylation of core histones, but whether TSA induces phosphorylation of core histones remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation at serine 28 and acetylation at lysine 9 of histone H3 induced by trichostatin A

et al. 2003

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Trichostatin A (TSA), a histone deacetylase inhibitor, strongly increases acetylation of the N-terminal tails of histone H3. Many studies have correlated the function of TSA with the hyperacetylation of histone. Although histone H3 is known to be phosphorylated, the effect of acetylation on phosphorylation is not known. Here, we report that in JB6 cells, TSA induces both acetylation at lysine 9 and phosphorylation at serine 28 of histone H3. UVB irradiation, which is known to induce phosphorylation at serine 28, did not significantly affect phosphorylation of histone H3 in TSA-pretreated JB6 cells. In contrast, TSA markedly increased phosphorylation and acetylation of histone H3 in UVB-pretreated JB6 cells. TSA strongly activated MAP kinases. Moreover, PD98059 and SB202190 inhibited TSA-induced phosphorylation but not acetylation of histone H3. Dominant negative mutant ERK2 and dominant negative mutant p38 kinase blocked TSA-stimulated phosphorylation of histone H3 at serine 28. The results indicate that TSAinduced phosphorylation of histone H3 at serine 28 occurs through activation of the MAP kinase pathway and phosphorylated histone H3 is more sensitive to TSAinduced hyperacetylation. The facilitation of phosphorylation and acetylation of histone H3 induced by TSA may play a critical regulatory role in chromatin remodeling and gene expression.

show abstract

Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin

Cited by 354 publications

References 47 publications

Cloning and Functional Characterization of HDAC11, a Novel Member of the Human Histone Deacetylase Family

Cloning and Functional Characterization of HDAC11, a Novel Member of the Human Histone Deacetylase Family

Acetylation of Steroidogenic Factor 1 Protein Regulates Its Transcriptional Activity and Recruits the Coactivator GCN5

Phosphorylation at serine 28 and acetylation at lysine 9 of histone H3 induced by trichostatin A

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