期刊
CELL CYCLE
卷 12, 期 23, 页码 3650-3662出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.26585
关键词
miR-29b; epi-miRNA; microRNA; multiple myeloma; methylation
类别
资金
- Italian Association for Cancer Research (AIRC) [9980]
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-kappa B 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.
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