Marisa Claudia Alvarez1, Victor Maso1, Cristiane Okuda Torello1, Karla Priscilla Ferro1, Sara Teresinha Olalla Saad2. 1. Hematology 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. 2. Hematology 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. sara@unicamp.br.
Abstract
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.
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.
Authors: Rainer Claus; Björn Hackanson; Anna R Poetsch; Manuela Zucknick; Miriam Sonnet; Nadja Blagitko-Dorfs; Jan Hiller; Stefan Wilop; Tim H Brümmendorf; Oliver Galm; Uwe Platzbecker; John C Byrd; Konstanze Döhner; Hartmut Döhner; Michael Lübbert; Christoph Plass Journal: Int J Cancer Date: 2011-11-28 Impact factor: 7.396
Authors: Victor Maso; Andrana Karla Calgarotto; Gilberto Carlos Franchi; Alexandre Eduardo Nowill; Paulo Latuf Filho; José Vassallo; Sara Teresinha Olalla Saad Journal: Cancer Prev Res (Phila) Date: 2014-10-07
Authors: Rocco Piazza; Vera Magistroni; Angela Mogavero; Federica Andreoni; Chiara Ambrogio; Roberto Chiarle; Luca Mologni; Petra S Bachmann; Richard B Lock; Paola Collini; Giuseppe Pelosi; Carlo Gambacorti-Passerini Journal: Neoplasia Date: 2013-05 Impact factor: 5.715