| Abstract: | Aberrant DNA methylation plays a relevant role in multiple myeloma (MM) pathogenesis. MicroRNAs
(miRNAs) are a class of small non-coding RNAs that recently emerged as master regulator of gene
expression by targeting protein-coding mRNAs. However, miRNAs involvement in the regulation of the
epigenetic machinery and their potential use as therapeutics in MM remain to be investigated. Here,
we provide evidence that the expression of de novo DNA methyltransferases (DNMTs) is deregulated in
MM cells. Moreover, we show that miR-29b targets DNMT3A and DNMT3B mRNAs and reduces global DNA
methylation in MM cells. In vitro transfection of MM cells with synthetic miR-29b mimics
significantly impairs cell cycle progression and also potentiates the growth-inhibitory effects
induced by the demethylating agent 5-azacitidine. Most importantly, in vivo intratumor or systemic
delivery of synthetic miR-29b mimics, in two clinically relevant murine models of human MM,
including the SCID-synth-hu system, induces significant anti-tumor effects. All together, our
findings demonstrate that aberrant DNMTs expression is efficiently modulated by tumor suppressive
synthetic miR-29b mimics, indicating that methyloma modulation is a novel matter of investigation in
miRNA-based therapy of MM. |
