Therapeutic targeting of miR-29b/HDAC4 epigenetic loop in multiple myeloma

Nicola Amodio, Maria Angelica Stamato, Anna Maria Gulla, Eugenio Morelli, Enrica Romeo, Lavinia Raimondi, Maria Rita Pitari, Ida Ferrandino, Gabriella Misso, Michele Caraglia, Ida Perrotta, Antonino Neri, Mariateresa Fulciniti, Christian Rolfo, Kenneth C. Anderson, Nikhil C. Munshi, Pierosandro Tagliaferri, Pierfrancesco Tassone

Research output: Contribution to journalArticle

Abstract

Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma, and their effects can be efficiently counteracted by a class of tumor suppressor miRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDAC) in multiple myeloma, we investigated whether their activity could be antagonized by miR-29b, a well-established epi-miRNA. We demonstrated here that miR-29b specifically targets HDAC4 and highlighted that both molecules are involved in a functional loop. In fact, silencing of HDAC4 by shRNAs inhibited multiple myeloma cell survival and migration and triggered apoptosis and autophagy, along with the induction of miR-29b expression by promoter hyperacetylation, leading to the downregulation of prosurvival miR-29b targets (SP1, MCL-1). Moreover, treatment with the pan-HDAC inhibitor SAHA upregulated miR-29b, overcoming the negative control exerted by HDAC4. Importantly, overexpression or inhibition of miR-29b, respectively, potentiated or antagonized SAHA activity on multiple myeloma cells, as also shown in vivo by a strong synergism between miR-29b synthetic mimics and SAHA in a murine xenograft model of human multiple myeloma. Altogether, our results shed light on a novel epigenetic circuitry regulating multiple myeloma cell growth and survival and open new avenues for miR-29b-based epi-therapeutic approaches in the treatment of this malignancy.

Original languageEnglish
Pages (from-to)1364-1375
Number of pages12
JournalMolecular Cancer Therapeutics
Volume15
Issue number6
DOIs
Publication statusPublished - Jun 1 2016

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Amodio, N., Stamato, M. A., Gulla, A. M., Morelli, E., Romeo, E., Raimondi, L., Pitari, M. R., Ferrandino, I., Misso, G., Caraglia, M., Perrotta, I., Neri, A., Fulciniti, M., Rolfo, C., Anderson, K. C., Munshi, N. C., Tagliaferri, P., & Tassone, P. (2016). Therapeutic targeting of miR-29b/HDAC4 epigenetic loop in multiple myeloma. Molecular Cancer Therapeutics, 15(6), 1364-1375. https://doi.org/10.1158/1535-7163.MCT-15-0985-T