Selective transcription and cellular proliferation induced by PDGF require histone deacetylase activity.
Histone deacetylases (HDACs) are key regulatory enzymes involved in the control of gene expression and their inhibition by specific drugs has been widely correlated to cell cycle arrest, terminal differentiation, and apoptosis. Here, we investigated whether HDAC activity was required for PDGF-dependent signal transduction and cellular proliferation. Exposure of PDGF-stimulated NIH3T3 fibroblasts to the HDAC inhibitor trichostatin A (TSA) potently repressed the expression of a group of genes correlated to PDGF-dependent cellular growth and pro-survival activity. Moreover, we show that TSA interfered with STAT3-dependent transcriptional activity induced by PDGF. Still, neither phosphorylation nor nuclear translocation and DNA-binding in vitro and in vivo of STAT3 were affected by using TSA to interfere with PDGF stimulation. Finally, TSA treatment resulted in the suppression of PDGF-dependent cellular proliferation without affecting cellular survival of NIH3T3 cells. Our data indicate that inhibition of HDAC activity antagonizes the mitogenic effect of PDGF, suggesting that these drugs may specifically act on the expression of STAT-dependent, PDGF-responsive genes.
Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università degli Studi di Napoli Federico II, Italy.
Annunziata
A
Catania
Carlo
C
Iavarone
Stella M
SM
Carlomagno
Mario
M
Chiariello
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010982:Platelet-Derived Growth Factor / Q000008:administration & dosage*; D050791:STAT Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects*
D010982:Platelet-Derived Growth Factor; D050791:STAT Transcription Factors; D006655:Histone Deacetylases