Genomic DNA Hypomethylation by Histone Deacetylase Inhibition Implicates DNMT1 Nuclear Dynamics

Abstract

Epigenetic modifications of chromatin play an important role in differentiation, aging, and tumorigenesis (41). Major epigenetic mechanisms include DNA methylation and covalent posttranslational modification of histone tails. These events switch chromatin between relatively "open" (expressed) and "closed" (suppressed) structures. Although there are several different histone modifications, the opposing activities of histone acetyl transferases (HATs) and histone deacetylases (HDACs) are considered important regulators of chromatin structure (28). DNA methylation is an important epigenetic modification in the vertebrate genome which occurs mainly on cytosines located in CpG dinucleotide sequences (2). DNA methylation patterns are established by DNA methyltransferase 3a (DNMT3a) and DNMT3b, which are de novo DNA methyltransferases (DNMTs), and are mainly propagated by DNMT1, a maintenance methyltransferase (39). DNA methyltransferases are involved in the aberrant DNA methylation patterns frequently found in cancer cells (21). In addition, there is growing evidence that inappropriate gene expression by epigenetic events is crucial for the initiation and progression of cancer. These epigenetic abnormalities, including epigenetic silencing of tumor suppressor genes by abnormal promoter methylation, are likely to play an important role in tumor growth and metastasis when a substantial number of genes can be inactivated by DNA methylation in a tumor (20). In addition to DNA methylation, genome-wide changes in histone modifications are also found in cancer cells. Loss of acetylation at lysine 16 and trimethylation at lysine 20 of histone H4 have been reported as common hallmarks of human cancer (11).New insights into the high prevalence of epigenetic changes in cancer have led to novel therapeutic approaches in oncology that rely on the dynamic nature of epigenetic factors. The main idea behind these approaches is that abnormal epigenetic marks leading to gene silencing may be reversed. Two categories of drugs, affecting histone acetylation and DNA methylation, are currently considered in epigenetic therapy of cancer. In myelodysplastic syndrome (MDS) and cutaneous T-cell lymphoma, DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) are already in clinical use (15,23). HDACi can open up chromatin by causing hyperacetylation of histones H3 and H4 (49). DNMTi, such as 5-aza-deoxycytidine, can induce genomic DNA hypomethylation (35). However, some gene promoters are not readily activated with either of the two inhibitors alone, but there are reports showing that HDACi and DNMTi can act synergistically to reactivate silenced genes (12,47). Therefore, the functional interaction between HDACs and DNMTs has been a key issue in epigenetic research. Trichostatin A (TSA), a general inhibitor for class I and II HDACs, has also been shown to reactivate methylation-silenced genes even in the absence of DNMT inhibitors (25). In addition, it has been reported that TSA decreases DNMT3b mRNA levels in endo...

Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL

“…This is not surprising as the majority of genes differentially methylated between azacitidine and combination treatment are shared. Romidepsin has a small effect on hypomethylation and this is in line with reports demonstrating the role of HDAC inhibition increasing global DNA hypomethylation (46,47). Interestingly, the combination treatment had an exclusive set of differentially methylated genes, which suggests specific pathways are involved in the synergistic action of romidepsin and azacitidine.…”

A unique histone deacetylase inhibitor alters microRNA expression and signal transduction in chemoresistant ovarian cancer cells

“…2 Even more impressively (but also controversially), several HDACIs have now been reported to reverse other (histone deacetylation-unrelated) repressive epigenetic modifications, including methylation of deoxycytosine, gain of gene-activating and/or loss of generepressive histone modifications (e.g., lysine methylation). [50][51][52] Regardless of the extent of HDACI epigenomic reprogramming, however, it is widely held that these agents will be most beneficial when combined with conventional and/or targeted therapies, as demonstrated by our group 6 and others. expression of multiple cytokeratins.…”

Epigenetic regulation of Dnmt3a and Arc gene expression after electroconvulsive stimulation in the rat

“…In another study, pre-treatment with the HDAC inhibitor phenylbutyric acid (PBA) prevented the ECS-induced decrease in c-Fos expression and reduced spatial memory deficits induced by ECS (Yao et al, 2010). The interplay between DNA methylation and histone modifications are highly interconnected and DNMT and HDAC inhibition also reduces global DNA methylation, DNMT1 protein levels, and its interaction with chromatin (Arzenani et al, 2011). Thus, the changes in Arc transcription following ECS are likely influenced by both DNA methylation and histone modifications.…”