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

Yu Yi Chu, Chiung Yuan Ko, Shao Ming Wang, Pin I. Lin, Han Ying Wang, W C Lin, Dong Yu Wu, Lu Hao Wang, Ju Ming Wang

研究成果: 雜誌貢獻文章

4 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)e3167
期刊Cell death & disease
8
發行號11
DOIs
出版狀態已發佈 - 十一月 9 2017

指紋

CCAAT-Enhancer-Binding Protein-delta
Gene Silencing
Yin-Yang
MicroRNAs
Epigenomics
Protein Methyltransferases
Leukemia
Apoptosis
DNA
5' Flanking Region
Cell Death
Polycomb-Group Proteins
DNA-Activated Protein Kinase
Ubiquitin-Conjugating Enzymes
CpG Islands
3' Untranslated Regions
Bortezomib
Pharmaceutical Preparations
Methylation
Genes

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

引用此文

Bortezomib-induced miRNAs direct epigenetic silencing of locus genes and trigger apoptosis in leukemia. / Chu, Yu Yi; Ko, Chiung Yuan; Wang, Shao Ming; Lin, Pin I.; Wang, Han Ying; Lin, W C; Wu, Dong Yu; Wang, Lu Hao; Wang, Ju Ming.

於: Cell death & disease, 卷 8, 編號 11, 09.11.2017, p. e3167.

研究成果: 雜誌貢獻文章

Chu, YY, Ko, CY, Wang, SM, Lin, PI, Wang, HY, Lin, WC, Wu, DY, Wang, LH & Wang, JM 2017, 'Bortezomib-induced miRNAs direct epigenetic silencing of locus genes and trigger apoptosis in leukemia', Cell death & disease, 卷 8, 編號 11, 頁 e3167. https://doi.org/10.1038/cddis.2017.520
Chu, Yu Yi ; Ko, Chiung Yuan ; Wang, Shao Ming ; Lin, Pin I. ; Wang, Han Ying ; Lin, W C ; Wu, Dong Yu ; Wang, Lu Hao ; Wang, Ju Ming. / Bortezomib-induced miRNAs direct epigenetic silencing of locus genes and trigger apoptosis in leukemia. 於: Cell death & disease. 2017 ; 卷 8, 編號 11. 頁 e3167.
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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.",
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T1 - Bortezomib-induced miRNAs direct epigenetic silencing of locus genes and trigger apoptosis in leukemia

AU - Chu, Yu Yi

AU - Ko, Chiung Yuan

AU - Wang, Shao Ming

AU - Lin, Pin I.

AU - Wang, Han Ying

AU - Lin, W C

AU - Wu, Dong Yu

AU - Wang, Lu Hao

AU - Wang, Ju Ming

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