The polyphenol quercetin induces cell death in leukemia by targeting epigenetic regulators of pro-apoptotic genes
Marisa Claudia Alvarez1, Victor Maso1, Cristiane Okuda Torello1
1Hematology and Transfusion Medicine Center-University of Campinas/Hemocentro-UNICAMP, Instituto Nacional de Ciencia e Tecnologia do Sangue, Rua Carlos Chagas, 480, CEP, Campinas, SP, 13083-878, Brazil.
Background:
In 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.
Results:
Qu 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).
Conclusions:
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 H3ac and H4ac in the promoter regions of genes involved in the apoptosis pathway, leading to their transcription activation.
Insights
Quercetin (Qu) induces apoptosis in acute myeloid leukemia by altering DNA methylation and histone modifications. This natural compound affects gene expression, promoting cancer cell death through epigenetic mechanisms.
Area of Science:
- Molecular Biology
- Epigenetics
- Cancer Research
Background:
- Quercetin (Qu) exhibits pro-apoptotic effects in cancer.
- The precise molecular mechanisms, particularly epigenetic alterations, remain to be fully elucidated.
Purpose of the Study:
- To investigate the impact of Qu treatment on DNA methylation and histone modifications in genes of the apoptosis pathway.
- To elucidate the molecular mechanisms behind Qu's pro-apoptotic effects in acute myeloid leukemia (AML).
Main Methods:
- In vivo studies using human xenograft AML models.
- In vitro studies using HL60 and U937 cell lines.
- Evaluation of DNA methylation (DNMT1, DNMT3a), histone modifications (HDACs, H3ac, H4ac), and gene expression.
Main Results:
- Qu treatment reduced DNMT1 and DNMT3a expression, partly mediated by STAT-3.
- Qu downregulated class I HDACs, with increased proteasomal degradation observed.
- Qu induced demethylation of BCL2L11 and DAPK1 genes.
- Qu treatment led to increased acetylation of histones H3 and H4 in the promoter regions of apoptosis-related genes (DAPK1, BCL2L11, BAX, APAF1, BNIP3, BNIP3L).
- Significant upregulation of mRNA levels for these apoptosis-related genes was observed post-Qu treatment.
Conclusions:
- Qu's pro-apoptotic effects in AML are partly attributed to DNA demethylation and HDAC inhibition.
- Qu enhances apoptosis by enriching acetylated histones H3 and H4 in the promoter regions of key apoptosis-related genes.
- These epigenetic modifications lead to the transcriptional activation of pro-apoptotic genes, contributing to cancer cell death.
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