Inhibition of EZH2 triggers the tumor suppressive miR-29b network in multiple myeloma

Maria Angelica Stamato, Giada Juli, Enrica Romeo, Domenica Ronchetti, Mariamena Arbitrio, Daniele Caracciolo, Antonino Neri, Pierosandro Tagliaferri, Pierfrancesco Tassone, Nicola Amodio

Research output: Contribution to journalArticle

Abstract

Downregulation of tumor suppressor (TS) microRNAs (miRNAs) commonly occurs in human cancer, including multiple myeloma (MM). We previously demonstrated that miR-29b is a relevant TS miRNA, whose expression in MM cells is inhibited by HDAC4-dependent deacetylation. Here, we provide novel insights into epigenetic mechanisms suppressing miR-29b in MM. In MM patient-derived plasma cells, we found inverse correlation between miR-29b and EZH2 mRNA expression. Both siRNAs and pharmacologic inhibitors of EZH2 led to miR-29b upregulation, and this effect was ascribed to reduced H3K27-trimethylation (H3K27me3) of miR-29a/b-1 promoter regions. Induction of miR-29b upon EZH2 inhibition occurred together with downregulation of major miR-29b pro-survival targets, such as SP1, MCL-1 and CDK6. Knock-down of the EZH2-interacting long non-coding RNA MALAT1 also reduced H3K27me3 of miR-29a/b-1 promoter, along with induction of miR-29b and downregulation of miR-29b targets. Importantly, inhibition of miR-29b by antagomiRs dramatically reduced in vitro anti-MM activity of small molecule EZH2-inhibitors, indicating that functional miR-29b is crucial for the activity of these compounds. Altogether, these results disclose novel epigenetic alterations contributing to the suppression of miR-29b molecular network, which can be instrumental for the development of rationally designed miRNA-based anti-MM therapeutics.

Original languageEnglish
Pages (from-to)106527-106537
Number of pages11
JournalOncotarget
Volume8
Issue number63
DOIs
Publication statusPublished - Jan 1 2017

Keywords

  • EZH2
  • MicroRNA
  • MiR-29b
  • MiRNA
  • Multiple myeloma

ASJC Scopus subject areas

  • Oncology

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    Stamato, M. A., Juli, G., Romeo, E., Ronchetti, D., Arbitrio, M., Caracciolo, D., Neri, A., Tagliaferri, P., Tassone, P., & Amodio, N. (2017). Inhibition of EZH2 triggers the tumor suppressive miR-29b network in multiple myeloma. Oncotarget, 8(63), 106527-106537. https://doi.org/10.18632/oncotarget.22507