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Therapeutic targeting of miR-29b/HDAC4 epigenetic loop in multiple myeloma.
Molecular Cancer Therapeutics 2016 March 29
Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma (MM), and their effects can be efficiently counteracted by a class of tumor suppressor microRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDACs) in MM, we investigated if their activity could be antagonized by miR-29b, a well-established epi-miRNA. We demonstrated here that miR-29b specifically targets HDAC4 and we highlighted that both molecules are involved in a functional loop. In fact, silencing of HDAC4 by shRNAs inhibited MM cell survival and migration and triggered apoptosis and autophagy, along with induction of miR-29b expression by promoter hyperacetylation, leading to downregulation of pro-survival 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 MM cells, as also shown in vivo by a strong synergism between miR-29b synthetic mimics and SAHA in a murine xenograft model of human MM. Altogether, our results shed light on a novel epigenetic circuitry regulating MM cell growth and survival, and open new avenues for miR-29b-based epi-therapeutic approaches in the treatment of this malignancy.
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