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Histone deacetylase inhibitors induce apoptosis, histone hyperacetylation and up-regulation of gene transcription in Schistosoma mansoni. 2009

Florence Dubois, and Stéphanie Caby, and Frédérik Oger, and Céline Cosseau, and Monique Capron, and Christoph Grunau, and Colette Dissous, and Raymond J Pierce
INSERM U 547, Institut Pasteur de Lille, IFR 142, 1 rue du Professeur A. Calmette, Lille, France.

In order to explore the conservation/divergence of transcriptional regulation in the platyhelminth parasite Schistosoma mansoni, we are studying the structures and functions of transcriptional mediators and in particular histone-modifying enzymes. Reversible histone acetylation changes chromatin structure and modulates gene transcription. The removal of acetyl residues from histones and other proteins is catalyzed by histone deacetylases (HDACs) that are under increasing study as therapeutic targets, both in cancer and parasitic diseases. In order to determine the extent and importance of histone acetylation in S. mansoni, we tested the effects of three histone deacetylase inhibitors (HDACi) on both larval and adult worms in culture. Trichostatin A (TSA), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) inhibited global HDAC activity at all life-cycle stages. TSA and VPA, but not SAHA, caused mortality of schistosomula and adults, with TSA showing the most rapid effect. Moreover, TSA caused an increase in apoptosis in schistosomula shown by the TUNEL assay and an increase in caspase 3/7 activity. Both TSA and VPA were shown to cause an increase in general levels of protein acetylation in schistosomes; more particularly of histone 4 whereas histone 3 acetylation was less affected. In the case of TSA treatment this histone hyperacetylation was correlated with the increased expression of caspases 3 and 7 transcripts. Finally, quantitative chromatin immunoprecipitation showed that the proximal promoter region of the S. mansoni caspase 7 gene was hyperacetylated on histone H4 after TSA treatment.

UI MeSH Term Description Entries
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006657 Histones Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. Histone,Histone H1,Histone H1(s),Histone H2a,Histone H2b,Histone H3,Histone H3.3,Histone H4,Histone H5,Histone H7
D006877 Hydroxamic Acids A class of weak acids with the general formula R-CONHOH. Hydroxamic Acid,Acid, Hydroxamic,Acids, Hydroxamic
D000077337 Vorinostat A hydroxamic acid and anilide derivative that acts as a HISTONE DEACETYLASE inhibitor. It is used in the treatment of CUTANEOUS T-CELL LYMPHOMA and SEZARY SYNDROME. 18F-SAHA,18F-Suberoylanilide Hydroxamic Acid,M344,MK-0683,MK0683,N-Hydroxy-N'-phenyloctanediamide,N1-Hydroxy-N8-phenyloctanediamide,NHNPODA,Suberanilohydroxamic Acid,Suberoyl Anilide Hydroxamic Acid,Suberoylanilide Hydroxamic Acid,Zolinza,18F Suberoylanilide Hydroxamic Acid,MK 0683,N Hydroxy N' phenyloctanediamide,N1 Hydroxy N8 phenyloctanediamide
D000107 Acetylation Formation of an acetyl derivative. (Stedman, 25th ed) Acetylations
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012550 Schistosoma mansoni A species of trematode blood flukes of the family Schistosomatidae. It is common in the Nile delta. The intermediate host is the planorbid snail. This parasite causes schistosomiasis mansoni and intestinal bilharziasis. Schistosoma mansonus,mansonus, Schistosoma
D014635 Valproic Acid A fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of EPILEPSY and BIPOLAR DISORDER. The mechanisms of its therapeutic actions are not well understood. It may act by increasing GAMMA-AMINOBUTYRIC ACID levels in the brain or by altering the properties of VOLTAGE-GATED SODIUM CHANNELS. Dipropyl Acetate,Divalproex,Sodium Valproate,2-Propylpentanoic Acid,Calcium Valproate,Convulsofin,Depakene,Depakine,Depakote,Divalproex Sodium,Ergenyl,Magnesium Valproate,Propylisopropylacetic Acid,Semisodium Valproate,Valproate,Valproate Calcium,Valproate Sodium,Valproic Acid, Sodium Salt (2:1),Vupral,2 Propylpentanoic Acid

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