DNA-demethylating and anti-tumor activity of synthetic miR-29b mimics in multiple myeloma

Nicola Amodio, Marzia Leotta, Dina Bellizzi, Maria Teresa Di Martino, Patrizia D'Aquila, Marta Lionetti, Fernanda Fabiani, Emanuela Leone, Anna Maria Gullà, Giuseppe Passarino, Michele Caraglia, Massimo Negrini, Antonino Neri, Antonio Giordano, Pierosandro Tagliaferri, Pierfrancesco Tassone

Research output: Contribution to journalArticle

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 expressionis 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. copy; Amodio et al.

Original languageEnglish
Pages (from-to)1246-1258
Number of pages13
JournalOncotarget
Volume3
Issue number10
Publication statusPublished - 2012

    Fingerprint

Keywords

  • DNA methyltransferases
  • DNMT
  • MicroRNA
  • Mir-29b
  • Multiple myeloma

ASJC Scopus subject areas

  • Oncology

Cite this

Amodio, N., Leotta, M., Bellizzi, D., Di Martino, M. T., D'Aquila, P., Lionetti, M., Fabiani, F., Leone, E., Gullà, A. M., Passarino, G., Caraglia, M., Negrini, M., Neri, A., Giordano, A., Tagliaferri, P., & Tassone, P. (2012). DNA-demethylating and anti-tumor activity of synthetic miR-29b mimics in multiple myeloma. Oncotarget, 3(10), 1246-1258.