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.

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

Stamato M. A.;Juli G.;Romeo E.;Arbitrio M.;Caracciolo D.;Neri A.;Tagliaferri P.;Tassone P.;Amodio N.
2017-01-01

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.
2017
EZH2
MicroRNA
MiR-29b
MiRNA
Multiple myeloma
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12317/79765
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