Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma.

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. Mol Cancer Ther; 15(6); 1364-75. ©2016 AACR.

journal_name

Mol Cancer Ther

authors

Amodio N,Stamato MA,Gullà AM,Morelli E,Romeo E,Raimondi L,Pitari MR,Ferrandino I,Misso G,Caraglia M,Perrotta I,Neri A,Fulciniti M,Rolfo C,Anderson KC,Munshi NC,Tagliaferri P,Tassone P

doi

10.1158/1535-7163.MCT-15-0985

subject

Has Abstract

pub_date

2016-06-01 00:00:00

pages

1364-75

issue

6

eissn

1535-7163

issn

1538-8514

pii

1535-7163.MCT-15-0985

journal_volume

15

pub_type

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