Research Papers:

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 _ and Nicola Amodio

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Oncotarget. 2017; 8:106527-106537. https://doi.org/10.18632/oncotarget.22507

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Maria Angelica Stamato1,*, Giada Juli1,*, Enrica Romeo1, Domenica Ronchetti2,3, Mariamena Arbitrio4, Daniele Caracciolo1, Antonino Neri2,3, Pierosandro Tagliaferri1, Pierfrancesco Tassone1,5 and Nicola Amodio1

1Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy

2Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy

3Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

4ISN-CNR, Roccelletta di Borgia, Catanzaro, Italy

5Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, US

*These authors contributed equally to this work

Correspondence to:

Pierfrancesco Tassone, email: [email protected]

Nicola Amodio, email: [email protected]

Keywords: miR-29b; microRNA; miRNA; multiple myeloma; EZH2

Received: August 31, 2017     Accepted: October 29, 2017     Published: November 20, 2017


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.

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