Abstract
BackgroundIn the present study, we investigated the molecular mechanisms underlying the pro-apoptotic effects of quercetin (Qu) by evaluating the effect of Qu treatment on DNA methylation and posttranslational histone modifications of genes related to the apoptosis pathway. This study was performed in vivo in two human xenograft acute myeloid leukemia (AML) models and in vitro using HL60 and U937 cell lines.ResultsQu treatment almost eliminates DNMT1 and DNMT3a expression, and this regulation was in part STAT-3 dependent. The treatment also downregulated class I HDACs. Furthermore, treatment of the cell lines with the proteasome inhibitor, MG132, together with Qu prevented degradation of class I HDACs compared to cells treated with Qu alone, indicating increased proteasome degradation of class I HDACS by Qu. Qu induced demethylation of the pro-apoptotic BCL2L11, DAPK1 genes, in a dose- and time-dependent manner. Moreover, Qu (50 μmol/L) treatment of cell lines for 48 h caused accumulation of acetylated histone 3 and histone 4, resulting in three- to ten fold increases in the promoter region of DAPK1, BCL2L11, BAX, APAF1, BNIP3, and BNIP3L. In addition, Qu treatment significantly increased the mRNA levels of all these genes, when compared to cells treated with vehicle only (control cells) (*p < 0.05).ConclusionsIn summary, our results showed that enhanced apoptosis, induced by Qu, might be caused in part by its DNA demethylating activity, by HDAC inhibition, and by the enrichment of H3ac and H4ac in the promoter regions of genes involved in the apoptosis pathway, leading to their transcription activation.
Highlights
We investigated the molecular mechanisms underlying the pro-apoptotic effects of Qu by evaluating the effect of Qu treatment on DNA methylation and posttranslational histone modifications of genes related to the apoptosis pathway
Quercetin decreases the protein expression of class I histone deacetylases (HDACs) in leukemia cells Given the data described and the fact that HADCs are found in corepressor complexes, we investigated whether the global increment of the acetylation of H3 and H4 affected the expression levels of HADCs
In summary, our results showed that enhanced apoptosis, induced by Qu, might be caused in part by its DNA demethylating activity, by HDAC inhibition, and by the enrichment of Acetylated histone 3 (H3ac) and Acetylated histone 4 (H4ac) in the promoter regions of genes involved in the apoptosis pathway, leading to their transcription activation
Summary
We investigated the molecular mechanisms underlying the pro-apoptotic effects of quercetin (Qu) by evaluating the effect of Qu treatment on DNA methylation and posttranslational histone modifications of genes related to the apoptosis pathway. This study was performed in vivo in two human xenograft acute myeloid leukemia (AML) models and in vitro using HL60 and U937 cell lines. Epigenetics, broadly, refers to stimuli-triggered changes in gene expression due to processes that arise independentless of changes in the underlying DNA sequence. Its study as potential therapeutic agent is assuming importance considering its involvement in the suppression of many tumor-related processes including oxidative stress, apoptosis, proliferation, and metastasis. Qu has received attention as a pro-apoptotic flavonoid with a specific and almost exclusive effect on tumor cell lines rather than normal, non-transformed cells [11]
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