Histone deacetylase inhibitors (HDACi) are promising antitumor drugs acting 
through reactivation of silenced tumor suppressor genes. Several HDACi are 
currently in clinical trials both for hematological and solid tissue 
malignancies. Cooperative action of HDACi and DNA methylation inhibitors (DNMTi) 
has been reported, making combined treatment an attractive choice for cancer 
therapy. There is some evidence that synergistic effects of HDACi and DNMTi are 
achieved by their action on common targets, including DNA methyltransferase 1 
(DNMT1). To further analyze this interaction, we investigated the effect of the 
HDACi trichostatin A on global and gene-specific DNA methylation and applied 
methods with single molecule sensitivity, confocal laser scanning microscopy 
with avalanche photodiode detectors (APD imaging) and fluorescence correlation 
spectroscopy (FCS), to study its effect on the nuclear dynamics of DNMT1 in live 
cells. Our data show that trichostatin A treatment reduces global DNA 
methylation and the DNMT1 protein level and alters DNMT1 nuclear dynamics and 
interactions with chromatin. The mechanisms underlying these effects are 
apparently distinct from the mechanisms of action of the DNMT inhibitor 
5-azacytidine. Our study sheds light on the molecular mechanisms underlying the 
synergistic action of HDACi and DNMTi and may also help to define improved 
policies for cancer treatment.