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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)e3167
JournalCell death & disease
Volume8
Issue number11
DOIs
Publication statusPublished - Nov 9 2017

ASJC Scopus subject areas

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

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    Chu, Y. Y., Ko, C. Y., Wang, S. M., Lin, P. I., Wang, H. Y., Lin, W. C., Wu, D. Y., Wang, L. H., & Wang, J. M. (2017). Bortezomib-induced miRNAs direct epigenetic silencing of locus genes and trigger apoptosis in leukemia. Cell death & disease, 8(11), e3167. https://doi.org/10.1038/cddis.2017.520