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Title
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Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma
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Author
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Abstract
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| 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. (C) 2016 AACR. |
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Language
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English
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Source (journal)
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Molecular cancer therapeutics. - Philadelphia, Pa
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Publication
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Philadelphia, Pa
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2016
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ISSN
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1535-7163
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DOI
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10.1158/1535-7163.MCT-15-0985-T
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Volume/pages
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15
:6
(2016)
, p. 1364-1375
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ISI
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000377427600021
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Full text (Publisher's DOI)
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