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At least 1,225 records · Page 68Linked to original sources
PubMed2005

Drug insight: Histone deacetylase inhibitors--development of the new targeted anticancer agent suberoylanilide hydroxamic acid.

This review focuses on the discovery and development of the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA). Post-translational modifications of the histones of chromatin are important factors in regulating gene expression--so-called epigenetic gene regulation. Acetylation and deacetylation of lysine residues in histone tails, controlled by the activities of HDACs and histone acetyltransferases, are among the most studied post-translational modification of histones. In addition to chromatin protein, transcription factors, cell-signaling regulatory proteins, and proteins regulating cell death are substrates of HDACs and may be altered in function by HDAC inhibitors. HDAC inhibitors have several remarkable aspects. For instance, despite HDACs being ubiquitously distributed through chromatin, SAHA selectively alters the transcription of relatively few genes, and normal cells are at least 10-fold more resistant than transformed cells to SAHA and related HDAC inhibitor-induced cell death. HDAC inhibitors represent a relatively new group of targeted anticancer compounds, which are showing significant promise as agents with activity against a broad spectrum of neoplasms, at doses that are well tolerated by cancer patients. SAHA is one of the HDAC inhibitors most advanced in development. It is in phase I and II clinical trials for patients with both hematologic and solid tumors.

Cell Death↗
PubMed2003

Histone deacetylases (HDACs): characterization of the classical HDAC family.

Transcriptional regulation in eukaryotes occurs within a chromatin setting, and is strongly influenced by the post-translational modification of histones, the building blocks of chromatin, such as methylation, phosphorylation and acetylation. Acetylation is probably the best understood of these modifications: hyperacetylation leads to an increase in the expression of particular genes, and hypoacetylation has the opposite effect. Many studies have identified several large, multisubunit enzyme complexes that are responsible for the targeted deacetylation of histones. The aim of this review is to give a comprehensive overview of the structure, function and tissue distribution of members of the classical histone deacetylase (HDAC) family, in order to gain insight into the regulation of gene expression through HDAC activity. SAGE (serial analysis of gene expression) data show that HDACs are generally expressed in almost all tissues investigated. Surprisingly, no major differences were observed between the expression pattern in normal and malignant tissues. However, significant variation in HDAC expression was observed within tissue types. HDAC inhibitors have been shown to induce specific changes in gene expression and to influence a variety of other processes, including growth arrest, differentiation, cytotoxicity and induction of apoptosis. This challenging field has generated many fascinating results which will ultimately lead to a better understanding of the mechanism of gene transcription as a whole.

Acetylation↗
PubMed2005

Epigenomic mapping in Arabidopsis using tiling microarrays.

In addition to genetic information, chromosomes transmit epigenetic information from cell to cell during division, and sometimes from generation to generation. While genetic information is encoded directly in the DNA sequence, epigenetic information is not, although it is usually associated with specific chromosomal regions. Epigenetic modifications in plants include cytosine methylation as well as modification of histones and other chromosomal proteins. Small interfering RNA play major roles in targeting these modifications to specific regions. Genomic tiling microarrays are powerful tools for analysing epigenetic information, and we review their application in building epigenomic maps in the model plant, Arabidopsis.

Arabidopsis↗
PubMed2003

Male-specific lethal complex of Drosophila targets activated regions of the X chromosome for chromatin remodeling.

The male-specific lethal (MSL) complex of Drosophila is responsible for the presence of a monoacetylated isoform of histone H4 (H4Ac16), found exclusively on the X chromosome of males. This particular covalent modification of histone H4 is correlated with a 2-fold enhancement of the transcription of most X-linked genes in Drosophila males, which is the basis of dosage compensation in this organism. Although widespread along the X chromosome, the MSL complex is not distributed uniformly, as can be seen by the indirect cytoimmunofluorescence staining of larval salivary-gland polytene chromosomes. This distribution pattern has been interpreted as a reflection of the tissue-specific transcriptional activity of the larval salivary gland and as an indication that the MSL complex associates with active chromatin. We have tested this hypothesis by comparing the chromosomal distribution of the complex in two different tissues. We performed this comparison by following the pattern of association of the complex at a specific site on salivary-gland chromosomes during larval development and determining whether an ectopic promoter located in a complex-devoid region of the X chromosome is able to attract the complex upon activation. Our results indicate that, in contrast to other chromatin-remodeling complexes that enhance transcription, the MSL complex targets active chromatin.

Acetylation↗
PubMed2004

A signaling role of histone-binding proteins and INHAT subunits pp32 and Set/TAF-Ibeta in integrating chromatin hypoacetylation and transcriptional repression.

Various post-translational modifications of histones significantly influence gene transcription. Although un- or hypoacetylated histones are tightly linked to transcriptional repression, the mechanisms and identities of chromatin signal transducer proteins integrating histone hypoacetylation into repression in humans have remained largely unknown. Here we show that the mammalian histone-binding proteins and inhibitor of acetyltransferases (INHAT) complex subunits, Set/template-activating factor-Ibeta (TAF-Ibeta) and pp32, specifically bind to unacetylated, hypoacetylated, and repressively marked histones but not to hyperacetylated histones. Additionally, Set/TAF-Ibeta and pp32 associate with histone deacetylases in vitro and in vivo and repress transcription from a chromatin-integrated template in vivo. Finally, Set/TAF-Ibeta and pp32 associate with an endogenous estrogen receptor-regulated gene, EB1, in the hypoacetylated transcriptionally inactive state but not with the hyperacetylated transcriptionally active form. Together, these data define a novel in vivo mechanistic role for the mammalian Set/TAF-Ibeta and pp32 proteins as transducers of chromatin signaling by integrating chromatin hypoacetylation and transcriptional repression.

Acetylation↗
PubMed2004

Trichostatin A extends the lifespan of Drosophila melanogaster by elevating hsp22 expression.

The level of acetylation of histones in nucleosomes is related to the longevity of yeast and animals. However, the mechanisms by which acetylation and deacetylation affect longevity remain unclear. In present study, we investigated the influence of histone acetylation modification on the expression of hsp22 gene and the lifespan in Drosophila melanogaster using histone deacetylase (HDAC) inhibitor Trichostatin A (TSA). The results showed that TSA could extend the lifespan of Drosophila melanogaster. Furthermore, TSA significantly promoted the hsp22 gene transcription, and affected the chromatin morphology at the locus of hsp22 gene along the polytene chromosome. Present data implicate that TSA may affect the lifespan of Drosophila through changing the level of histone acetylation and influencing the expression of hsp22 gene that is related to aging.

Acetylation↗
PubMed1993

Protein glycation by ADP-ribose: studies of model conjugates.

Protein glycation by hexoses has been implicated in the pathophysiology of a number of diseases as well as the aging process. Studies of ADP-ribose polymer metabolism have shown that free ADP-ribose is generated at high rates in the cell nucleus following DNA damage. Protein glycation by ADP-ribose has been reported although the chemistry is not understood. Described here is the synthesis and characterization of model conjugates for protein glycation of lysine residues by ADP-ribose. Two stable conjugates derived from ADP-ribose and n-butylamine were isolated and characterized. Both conjugates were shown to be ketoamines derived from a Schiff base by an Amadori rearrangement. The chemical stability of the ketamines allowed them to be differentiated from all classes of enzymic protein modification by ADP-ribose. Further, their chemical properties suggest that a previous report of histone H1 modification in carcinogen treated cells was due to glycation by ADP-ribose.

Adenosine Diphosphate Ribose↗
PubMed2005

Truncation, deamidation, and oxidation of histone H2B in cells cultured with nickel(II).

Molecular mechanisms of nickel-induced carcinogenesis include interactions of Ni(II) cations with histones. Previously, we demonstrated in vitro and in cells that Ni(II) cleaved off the -SHHKAKGK C-terminal motif of histone H2A. In the present study, Western blotting of histones isolated from rat and human cell lines, cultured for 3-5 days with 0.05-0.5 mM Ni(II), revealed time- and dose-dependent appearance of a new band of histone H2B. This effect was also induced by Co(II), but not by Cu(II), Cd(II), and Zn(II). Mass spectrometry and amino acid sequencing of proteins from the new band allowed for identification of two derivatives of the major variant of histone H2B. The larger protein was histone H2B lacking 16 N-terminal amino acids. The smaller one was histone H2B which, in addition to being shortened at the N-terminus, had nine amino acids deleted from its C-terminus. At both termini, the truncation occurred between lysine and alanine in the two identical -KAVTK- repeats of histone H2B. Also, the truncated H2B proteins had their Q22 residues deamidated and M59 and M62 residues oxidized to sulfoxides, a signature of oxidative stress. The truncation did not concur with apoptosis. Its mechanism involved activation by Ni(II) treatment of specific nuclear proteolytic enzymes belonging to the calpain family. The terminal tails of core histones participate in structuring chromatin and regulating gene expression. Therefore, the observed truncation and other modifications of histone H2B may assist in Ni(II) carcinogenesis through epigenetic mechanisms.

Animals↗
PubMed1991

Postsynthetic methylation of core histones in K562 cells is associated with bulk acetylation but not with transcriptional activity.

The relationship between the postsynthetic modification of core histones by methylation and transcriptionally active chromatin was investigated in K562 erythroleukemia cells. Cells were incubated with L-[methyl-3H]methionine in the presence of cycloheximide. Under these conditions, only histones H3 and H4 were detectably methylated. Chromatin was fractionated by several methods, including low-salt elution, mononucleosome gel mobility shift using HPLC-purified HMG 17, and cesium chloride-guanidine equilibrium gradient centrifugation of formaldehyde-fixed chromatin. By these latter two methods, chromatin highly enriched for transcriptionally engaged or competent genes was isolated. A significant correlation was noted between postsynthetic modification of histones by methylation and by the slow-turnover form of acetylation. However, there was no enrichment of methylated histones in the transcriptionally competent fraction of chromatin isolated by HMG 17 binding. Moreover, only minor enrichment of methylated histone H3.1 and no enrichment of methylated histones H3.2 and H4 was detected in transcriptionally engaged chromatin isolated by gradient centrifugation. Chromatin soluble in low-salt buffer was found to be significantly enriched in methylated histones, but not in active genes. We conclude that histone methylation is associated with both transcriptionally active and transcriptionally inactive chromatin. The function of this modification, like that of bulk histone acetylation, remains to be determined.

Acetylation↗
PubMed2001

Protein modules that manipulate histone tails for chromatin regulation.

Histones are the predominant protein components of chromatin and are subject to specific post-translational modifications that are correlated with transcriptional competence. Among these histone modifications are acetylation, phosphorylation and methylation, and recent studies reveal that conserved protein modules mediate the attachment, removal or recognition of these modifications. It is becoming clear that appropriate coordination of histone modifications and their manipulations by conserved protein modules are integral to gene-specific transcriptional regulation within chromatin.

Animals↗
PubMed2004

Histone deacetylase activity is required to recruit RNA polymerase II to the promoters of selected interferon-stimulated early response genes.

Posttranslational modification of histones by acetylation, methylation or phosphorylation has emerged as a major mechanism to modify chromatin structure and gene expression. In most cases, transcriptionally active genes display enhanced binding of acetylated histones in their promoters. Activation of histone acetyltransferases or inhibition of histone deacetylases (HDACs) allows chromatin to assume a more open state permitting transcriptional activators to form a preinitiation complex. To our surprise, treatment of cells with the HDAC inhibitor, trichostatin A (TSA), inhibits selected interferon beta (IFNbeta)-stimulated immediate early genes that are activated by the transcription factors Stat1 and Stat2. However, IFNbeta activation of IRF-1, which requires tyrosine-phosphorylated Stat1 homodimers binding to a gamma interferon activation sequence in its promoter is not affected by TSA. Exposure of cells to TSA does not alter tyrosine phosphorylation of Stat1 or Stat2. TSA treatment of cells also does not alter the binding of Stat 1 or Stat2 to the endogenous ISG54 promoter. However, IFNbeta-stimulated binding of RNA polymerase II to the ISG54 promoter is prevented by TSA. Interestingly, ectopic expression of IRF9 reverses the inhibitory actions of TSA, suggesting that IRF9 functions to recruit RNA polymerase II to the promoter of interferon-stimulated genes. This particular function of IRF9 requires the activity of histone deacetylases.

Cell Line↗
PubMed2005

Rational development of histone deacetylase inhibitors as anticancer agents: a review.

The epigenome is defined by DNA methylation patterns and the associated post-translational modifications of histones. This histone code determines the expression status of individual genes dependent upon their localization on the chromatin. The histone deacetylases (HDACs) play a major role in keeping the balance between the acetylated and deacetylated states of chromatin and eventually regulate gene expression. Recent developments in understanding the cancer cell cycle, specifically the interplay with chromatin control, are providing opportunities for developing mechanism-based therapeutic drugs. Inhibitors of HDACs are under considerable exploration, in part because of their potential roles in reversing the silenced genes in transformed tumor cells by modulating transcriptional processes. This review is an effort to summarize the nonclinical and clinical status of HDAC inhibitors currently under development in anticancer therapy.

Animals↗
PubMed2004

Histone deacetylase inhibitors--a new tool to treat cancer.

Transcriptional regulation in eukaryotes is a multilevel hierarchical process. It is becoming clear that higher-order chromatin structure, occurring via modifications of histones in their nucleosome structure, plays a crucial role in regulating gene expression, both in normal and pathological states. Deacetylation of histones by histone deacetylases (HDACs) modifies the chromatin from an open gene active euchromatin structure to a closed gene silenced heterochromatin structure. Several cancer promoting mutations and chromosomal translocations result in repression of transcription through abnormal recruitment and activation of HDACs, leading to neoplastic transformation. This is the rationale for the evolvement of HDAC inhibitors as a new class in cancer therapy. Trials have shown anti-proliferation effect of histone deacetylase inhibitors in cell culture, animal models and in human with both hematological and solid tumors. The exact mechanism by which histone deacetylase inhibitors exert their effect is still obscure. Reversal of the alteration in gene expression by fusion transcription factors or overexpressed repressors is just one of several possible explanations. The territory of heterochromatin in the vicinity of the nuclear periphery raised the possibility of involvement of nuclear envelope proteins in the regulation of transcription. Our laboratory is interested in the transcription repression mechanism induced by the nuclear envelope lamina associated polypeptide 2 (LAP2) family of proteins through chromatin modification. Here, we will describe the structure of the nucleosome, review regulation of gene expression by acetylation of histones and give an update on the current phase I and phase II clinical trials with histone deacetylase inhibitors.

Acetylation↗
PubMed2005

Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications.

The class II deacetylase histone deacetylase 4 (HDAC4) negatively regulates the transcription factor MEF2. HDAC4 is believed to repress MEF2 transcriptional activity by binding to MEF2 and catalyzing local histone deacetylation. Here we report that HDAC4 also controls MEF2 by a novel SUMO E3 ligase activity. We show that HDAC4 interacts with the SUMO E2 conjugating enzyme Ubc9 and is itself sumoylated. The overexpression of HDAC4 leads to prominent MEF2 sumoylation in vivo, whereas recombinant HDAC4 stimulates MEF2 sumoylation in a reconstituted system in vitro. Importantly, HDAC4 promotes sumoylation on a lysine residue that is also subject to acetylation by a MEF2 coactivator, the acetyltransferase CBP, suggesting a possible interplay between acetylation and sumoylation in regulating MEF2 activity. Indeed, MEF2 acetylation is correlated with MEF2 activation and dynamically induced upon muscle cell differentiation, while sumoylation inhibits MEF2 transcriptional activity. Unexpectedly, we found that HDAC4 does not function as a MEF2 deacetylase. Instead, the NAD+-dependent deacetylase SIRT1 can potently induce MEF2 deacetylation. Our studies reveal a novel regulation of MEF2 transcriptional activity by two distinct classes of deacetylases that affect MEF2 sumoylation and acetylation.

Acetylation↗
PubMed2002

The histone deacetylase inhibitor trichostatin A blocks progesterone receptor-mediated transactivation of the mouse mammary tumor virus promoter in vivo.

Post-translational modifications of histones play an important role in modulating gene transcription within chromatin. We used the mouse mammary tumor virus (MMTV) promoter, which adopts an ordered nucleosomal structure, to investigate the impact of a specific inhibitor of histone deacetylase, trichostatin A (TSA), on progesterone receptor-activated transcription. TSA induced global histone hyperacetylation, and this effect occurred independently of the presence of hormone. Interestingly, chromatin immunoprecipitation analysis revealed no significant change in the level of acetylated histones associated with the MMTV promoter following high TSA treatment. In human breast cancer cells, in which the MMTV promoter adopts a constitutively "open" chromatin structure, treatment with TSA converted the MMTV promoter into a closed structure. Addition of hormone did not overcome this TSA-induced closure of the promoter chromatin. Furthermore, TSA treatment resulted in the eviction of the transcription factor nuclear factor-1 from the promoter and reduced progesterone receptor-induced transcription. Kinetic experiments revealed that a loss of chromatin-remodeling proteins was coincident with the decrease in MMTV transcriptional activity and the imposition of repressed chromatin architecture at the promoter. These results demonstrate that deacetylase inhibitor treatment at levels that induce global histone acetylation may leave specific regulatory regions relatively unaffected and that this treatment may lead to transcriptional inhibition by mechanisms that modify chromatin-remodeling proteins rather than by influencing histone acetylation of the local promoter chromatin structure.

Acetylation↗
PubMed2002

SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins.

Posttranslational modification of histones has emerged as a key regulatory signal in eukaryotic gene expression. Recent genetic and biochemical studies link H3-lysine 9 (H3-K9) methylation to HP1-mediated heterochromatin formation and gene silencing. However, the mechanisms that target and coordinate these activities to specific genes is poorly understood. Here we report that the KAP-1 corepressor for the KRAB-ZFP superfamily of transcriptional silencers binds to SETDB1, a novel SET domain protein with histone H3-K9-specific methyltransferase activity. Although acetylation and phosphorylation of the H3 N-terminal tail profoundly affect the efficiency of H3-K9 methylation by SETDB1, we found that methylation of H3-K4 does not affect SETDB1-mediated methylation of H3-K9. In vitro methylation of the N-terminal tail of histone H3 by SETDB1 is sufficient to enhance the binding of HP1 proteins, which requires both an intact chromodomain and chromoshadow domain. Indirect immunofluoresence staining of interphase nuclei localized SETDB1 predominantly in euchromatic regions that overlap with HP1 staining in nonpericentromeric regions of chromatin. Moreover, KAP-1, SETDB1, H3-MeK9, and HP1 are enriched at promoter sequences of a euchromatic gene silenced by the KRAB-KAP-1 repression system. Thus, KAP-1 is a molecular scaffold that is targeted by KRAB-ZFPs to specific loci and coordinates both histone methylation and the deposition of HP1 proteins to silence gene expression.

Animals↗
PubMed2000

Regulation of chromatin structure by site-specific histone H3 methyltransferases.

The organization of chromatin into higher-order structures influences chromosome function and epigenetic gene regulation. Higher-order chromatin has been proposed to be nucleated by the covalent modification of histone tails and the subsequent establishment of chromosomal subdomains by non-histone modifier factors. Here we show that human SUV39H1 and murine Suv39h1--mammalian homologues of Drosophila Su(var)3-9 and of Schizosaccharomyces pombe clr4--encode histone H3-specific methyltransferases that selectively methylate lysine 9 of the amino terminus of histone H3 in vitro. We mapped the catalytic motif to the evolutionarily conserved SET domain, which requires adjacent cysteine-rich regions to confer histone methyltransferase activity. Methylation of lysine 9 interferes with phosphorylation of serine 10, but is also influenced by pre-existing modifications in the amino terminus of H3. In vivo, deregulated SUV39H1 or disrupted Suv39h activity modulate H3 serine 10 phosphorylation in native chromatin and induce aberrant mitotic divisions. Our data reveal a functional interdependence of site-specific H3 tail modifications and suggest a dynamic mechanism for the regulation of higher-order chromatin.

Amino Acid Sequence↗
PubMed2005

[Epigenetics and cancer].

Epigenetics is defined as "the study of mitotically and/or meiotically heritable changes in gene expression that cannot be explained by changes in the DNA sequence". Setting up the epigenetic program is crucial for correct development and its stable inheritance throughout its lifespan is essential for the maintenance of the tissue- and cell-specific functions of the organism. For many years, the genetic causes of cancer have hold centre stage. However, the recent wealth of information about the molecular mechanisms which, by modulating the chromatin structure, can regulate gene expression has high-lighted the predominant role of epigenetic modifications in the initiation and progression of numerous pathologies, including cancer. The nucleosome is the major target of these epigenetic regulation mechanisms. They include a series of tightly interconnected steps which starting with the setting ("writing") of the epigenetic mark till its "reading" and interpretation will result in long-term gene regulation. The major epigenetic changes associated with tumorigenesis are aberrant DNA methylation of CpG islands located in the promoter region of tumor suppressor gene, global genomic hypomethylation and covalent modifications of histone N-terminal tails which are protruding out from the nucleosome core. In sharp contrast with genetic modifications, epigenetic modifications are highly dynamic and reversible. The characterization of specific inhibitors directed against some key epigenetic players has opened a new and promising therapeutic avenue, the epigenetic therapy, since some inhibitors are already used in clinical trials.

Animals↗