Bortezomib-induced miRNAs direct epigenetic silencing of locus genes and trigger apoptosis in leukemia.

Abstract

MicroRNAs (miRNAs) have been suggested to repress transcription via binding the 3'-untranslated regions of mRNAs. However, the involvement and details of miRNA-mediated epigenetic regulation, particularly in targeting genomic DNA and mediating epigenetic regulation, remain largely uninvestigated. In the present study, transcription factor CCAAT/enhancer binding protein delta (CEBPD) was responsive to the anticancer drug bortezomib, a clinical and highly selective drug for leukemia treatment, and contributed to bortezomib-induced cell death. Interestingly, following the identification of CEBPD-induced miRNAs, we found that miR-744, miR-3154 and miR-3162 could target CpG islands in the 5'-flanking region of the CEBPD gene. We previously demonstrated that the Yin Yang 1 (YY1)/polycomb group (PcG) protein/DNA methyltransferase (DNMT) complex is important for CCAAT/enhancer binding protein delta (CEBPD) gene inactivation; we further found that Argonaute 2 (Ago2) interacts with YY1 and binds to the CEBPD promoter. The miRNA/Ago2/YY1/PcG group protein/DNMT complex linked the inactivation of CEBPD and genes adjacent to its 5'-flanking region, including protein kinase DNA-activated catalytic polypeptide (PRKDC), minichromosome maintenance-deficient 4 (MCM4) and ubiquitin-conjugating enzyme E2 variant 2 (UBE2V2), upon bortezomib treatment. Moreover, we revealed that miRNA binding is necessary for YY1/PcG group protein/DNMT complex-mediated epigenetic gene silencing and is associated with bortezomib-induced methylation on genomic DNA. The present study successfully characterized the interactions of the miRNA/Ago2/YY1/PcG group protein/DNMT complex and provided new insights for miRNA-mediated epigenetic regulation in bortezomib-induced leukemic cell arrest and cell death.

• Authors: Yu-Yi Chu, Chiung-Yuan Ko, Shao-Ming Wang, Pin-I Lin, Han-Ying Wang, Wen-Chi Lin, Dong-Yu Wu, Lu-Hao Wang, Ju-Ming Wang
• Journal: Cell death & disease (Cell Death Dis) Vol. 8 Issue 11 Pg. e3167 (11 09 2017) ISSN: 2041-4889 [Electronic] England
• PMID: 29120412 (Publication Type: Journal Article)

Chemical References

• 3' Untranslated Regions
• AGO2 protein, human
• Antineoplastic Agents
• Argonaute Proteins
• MicroRNAs
• Nuclear Proteins
• YY1 Transcription Factor
• YY1 protein, human
• CCAAT-Enhancer-Binding Protein-delta
• Bortezomib
• UBE2V2 protein, human
• Ubiquitin-Conjugating Enzymes
• DNA-Activated Protein Kinase
• PRKDC protein, human
• MCM4 protein, human
• Minichromosome Maintenance Complex Component 4
• Ligases

Topics

• 3' Untranslated Regions
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Argonaute Proteins (chemistry, metabolism)
• Bortezomib (pharmacology)
• CCAAT-Enhancer-Binding Protein-delta (genetics, metabolism)
• Cell Line, Tumor
• CpG Islands
• DNA Methylation (drug effects)
• DNA-Activated Protein Kinase (genetics, metabolism)
• Gene Silencing
• Humans
• Leukemia (metabolism, physiopathology)
• Ligases (genetics, metabolism)
• MicroRNAs (genetics, metabolism)
• Minichromosome Maintenance Complex Component 4 (genetics, metabolism)
• Nuclear Proteins (genetics, metabolism)
• Promoter Regions, Genetic
• Protein Binding
• Transcription, Genetic (drug effects)
• Ubiquitin-Conjugating Enzymes
• YY1 Transcription Factor (chemistry, metabolism)