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.
Highlights
Multiple myeloma (MM) is the second most common hematological cancer worldwide and is characterized by progressive accumulation of tumor plasma cells (PC) in the bone marrow (BM), paraprotein production, renal failure and bone destruction [1].Research carried out in the last decade has disclosed an unprecedented role of the non-coding genome in PC biology, as well as its relevant contribution to cell transformation in the context of PC dyscrasias [2,3,4]
We previously demonstrated that miR-29b is a relevant tumor suppressor (TS) miRNA, whose expression in MM cells is inhibited by HDAC4-dependent deacetylation
In an attempt to identify novel epigenetic regulators contributing to the silencing of TS miR-29b in MM, firstly we evaluated the potential correlation between miR-29b and the mRNA expression levels of histone methyltransferases with an oncogenic role in MM [23], such as EZH1, EZH2 and MMSET
Summary
Multiple myeloma (MM) is the second most common hematological cancer worldwide and is characterized by progressive accumulation of tumor plasma cells (PC) in the bone marrow (BM), paraprotein production, renal failure and bone destruction [1].Research carried out in the last decade has disclosed an unprecedented role of the non-coding genome in PC biology, as well as its relevant contribution to cell transformation in the context of PC dyscrasias [2,3,4]. Among non-coding RNAs, to date the best characterized class is represented by microRNAs (miRNAs), short noncoding RNAs that post-transcriptionally regulate gene www.impactjournals.com/oncotarget expression by binding to the 3′ UTR of mRNA targets, triggering mRNA and/or protein degradation [2, 5]. MiRNAs can regulate several signal transduction pathways involved in MM pathogenesis [6, 7]. Depending on their mRNA targets, miRNAs can act either as oncogenes [8,9,10,11,12,13] or as tumor suppressor (TS) miRNAs [14,15,16], which finely tune the interaction between MM cells and the BM milieu [3, 17]. In MM cells, ectopic miR29b was shown to downregulate major tumor promoting or anti-apoptotic mRNA targets, including CDK6, MCL-1, SP1 [14], as well as mRNAs coding for epigenetic regulators, such as HDAC4 [19] and DNMT3A/B [20], triggering cell cycle arrest and apotosis
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