The polyphenol quercetin induces cell death in leukemia by targeting epigenetic regulators of pro-apoptotic genes

Autor(es)

Alvarez, Marisa Claudia ^[1] ; Maso, Victor ^[1] ; Torello, Cristiane Okuda ^[1] ; Ferro, Karla Priscilla ^[1] ; Olalla Saad, Sara Teresinha ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Hematol & Transfus Med Ctr, Inst Nacl Ciencia & Tecnol Sangue, Hemoctr, UNICAMP, Rua Carlos Chagas 480, BR-13083878 Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CLINICAL EPIGENETICS; v. 10, NOV 8 2018.
• Citações Web of Science: 5

Resumo

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 (50mol/L) treatment of cell lines for 48h caused accumulation of acetylated histone 3 and histone 4, resulting in three- to tenfold 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. (AU)

• Processo FAPESP: 15/21164-7 - Análise dos mecanismos pelos quais os polifenóis Quercetina e Epigalocatequina 3- galato modulam as alterações epigenéticas presentes nas síndromes mielodisplásicas e leucemias
• Beneficiário: Marisa Claudia Alvarez de Prax
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado