Histone deacetylase inhibitors induce apoptosis, histone hyperacetylation and up-regulation of gene transcription in Schistosoma mansoni.
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.
Dubois
Florence
F
INSERM U 547, Institut Pasteur de Lille, IFR 142, 1 rue du Professeur A. Calmette, Lille, France.
Caby
Stéphanie
S
Oger
Frédérik
F
Cosseau
Céline
C
Capron
Monique
M
Grunau
Christoph
C
Dissous
Colette
C
Pierce
Raymond J
RJ
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000096:biosynthesis; D053179:Caspase 7 / Q000096:biosynthesis; D047369:Chromatin Immunoprecipitation; D016054:DNA, Protozoan / Q000737:chemistry / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D008969:Molecular Sequence Data; D012550:Schistosoma mansoni / Q000187:drug effects*; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D015854:Up-Regulation; D014635:Valproic Acid / Q000494:pharmacology; D000077337:Vorinostat
D016054:DNA, Protozoan; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A; D000077337:Vorinostat; D014635:Valproic Acid; D053148:Caspase 3; D053179:Caspase 7