Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma
Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma
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DOI：
10.1158/1535-7163.mct-15-0985-t
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发表时间：
2016-06-01
影响因子：
5.7
通讯作者：
Tassone, Pierfrancesco
中科院分区：
文献类型：
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作者：
Amodio, Nicola;Stamato, Maria Angelica;Tassone, Pierfrancesco
表观遗传异常在包括多发性骨髓瘤在内的血液恶性肿瘤中很常见，并且它们的作用可以被一类称为epi-miRNAs的肿瘤抑制miRNAs有效抵消。鉴于组蛋白去乙酰化酶（HDAC）在多发性骨髓瘤中的致癌作用，我们研究了它们的活性是否可以被miR-29 b（一种成熟的epi-miRNA）拮抗。我们在这里证明了miR-29 b特异性靶向HDAC 4，并强调了这两种分子都参与了功能环。事实上，通过shRNA沉默HDAC 4抑制多发性骨髓瘤细胞存活和迁移，并引发细胞凋亡和自噬，沿着通过启动子过度乙酰化诱导miR-29 b表达，导致促存活miR-29 b靶点（SP1，MCL-1）下调。此外，用泛HDAC抑制剂SAHA处理上调miR-29 b，克服了HDAC 4施加的阴性对照。重要的是，miR-29 b的过表达或抑制分别增强或拮抗SAHA对多发性骨髓瘤细胞的活性，如在人多发性骨髓瘤的鼠异种移植模型中miR-29 b合成模拟物和SAHA之间的强协同作用在体内也显示的。总之，我们的研究结果揭示了一种新的表观遗传电路调节多发性骨髓瘤细胞的生长和存活，并为基于miR-29 b的表观治疗方法在治疗这种恶性肿瘤中开辟了新的途径。(C)2016年AACR。
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.