miR-29b induces SOCS-1 expression by promoter demethylation and negatively regulates migration of multiple myeloma and endothelial cells

Nicola Amodio, Dina Bellizzi, Marzia Leotta, Lavinia Raimondi, Lavinia Biamonte, Patrizia D'Aquila, Maria Teresa Di Martino, Teresa Calimeri, Marco Rossi, Marta Lionetti, Emanuela Leone, Giuseppe Passarino, Antonino Neri, Antonio Giordano, Pierosandro Tagliaferri, Pierfrancesco Tassone

Research output: Contribution to journalArticle

Abstract

Epigenetic silencing of tumor suppressor genes frequently occurs and may account for their inactivation in cancer cells. We previously demonstrated that miR-29b is a tumor suppressor microRNA (miRNA) that targets de novo DNA methyltransferases and reduces the global DNA methylation of multiple myeloma (MM) cells. Here, we provide evidence that epigenetic activity of miR-29b leads to promoter demethylation of suppressor of cytokine signaling-1 (SOCS-1), a hypermethylated tumor suppressor gene. Enforced expression of synthetic miR-29b mimics in MM cell lines resulted in SOCS-1 gene promoter demethylation, as assessed by Sequenom MassARRAY EpiTYPER analysis, and SOCS-1 protein upregulation. miR-29b-induced SOCS-1 demethylation was associated with reduced STAT3 phosphorylation and impaired NF-κB activity. Downregulation of VEGF-A and IL-8 mRNAs could be detected in MM cells transfected with miR-29b mimics as well as in endothelial (HUVEC) or stromal (HS-5) cells treated with conditioned medium from miR-29b-transfected MM cells. Notably, enforced expression of miR-29b mimics increased adhesion of MM cells to HS-5 and reduced migration of both MM and HUVEC cells. These findings suggest that miR-29b is a negative regulator of either MM or endothelial cell migration. Finally, the proteasome inhibitor bortezomib, which induces the expression of miR-29b, decreased global DNA methylation by a miR-29b-dependent mechanism and induced SOCS-1 promoter demethylation and protein upregulation. In conclusion, our data indicate that miR-29b is endowed with epigenetic activity and mediates previously unknown functions of bortezomib in MM cells.

Original languageEnglish
Pages (from-to)3650-3662
Number of pages13
JournalCell Cycle
Volume12
Issue number23
DOIs
Publication statusPublished - Dec 1 2013

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Keywords

  • epi-miRNA
  • Methylation
  • microRNA
  • miR-29b
  • Multiple myeloma

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

Amodio, N., Bellizzi, D., Leotta, M., Raimondi, L., Biamonte, L., D'Aquila, P., Di Martino, M. T., Calimeri, T., Rossi, M., Lionetti, M., Leone, E., Passarino, G., Neri, A., Giordano, A., Tagliaferri, P., & Tassone, P. (2013). miR-29b induces SOCS-1 expression by promoter demethylation and negatively regulates migration of multiple myeloma and endothelial cells. Cell Cycle, 12(23), 3650-3662. https://doi.org/10.4161/cc.26585