Myc Induces miRNA-Mediated Apoptosis in Response to HDAC Inhibition in Hematologic Malignancies.
Myc Induces miRNA-Mediated Apoptosis in Response to HDAC Inhibition in Hematologic Malignancies.
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DOI：
10.1158/0008-5472.can-15-1751
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发表时间：
2016-02-01
期刊：
影响因子：
11.2
通讯作者：
Eischen CM
中科院分区：
文献类型：
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作者：
Adams CM;Hiebert SW;Eischen CM
组蛋白去乙酰化酶（hdac）表达或功能的改变有助于血液恶性肿瘤的发生和进展。因此，HDAC抑制剂的开发和实施已被证明在治疗上是有益的，特别是对血液系统恶性肿瘤。然而，HDAC抑制（HDACi）诱导肿瘤细胞死亡的分子机制尚不清楚。在这里，我们研究了HDACi在myc驱动的b细胞淋巴瘤和其他五种造血恶性肿瘤中的作用。我们确定Myc介导的恶性细胞中miR-15和let-7家族的转录抑制在HDACi后得到缓解，并且Myc是其上调所必需的。然后，miR-15和let-7家族分别靶向并下调抗凋亡基因Bcl-2和Bcl-xL，诱导hdac介导的细胞凋亡。值得注意的是，在未转化的细胞中，Myc也通过转录上调了这些miRNA，这表明Myc诱导的miRNA介导的凋亡途径在恶性细胞中被抑制，但在HDACi时被重新激活。综上所述，我们的研究结果揭示了Myc在恶性造血细胞中诱导凋亡的一种先前未知的机制，该机制独立于p53途径，并作为对HDACi的反应。
Alterations in the expression or function of histone deacetylases (HDACs) contribute to the development and progression of hematologic malignancies. Consequently, the development and implementation of HDAC inhibitors has proven to be therapeutically beneficial, particularly for hematologic malignancies. However, the molecular mechanisms by which HDAC inhibition (HDACi) induces tumor cell death remain unresolved. Here, we investigated the effects of HDACi in Myc-driven B-cell lymphoma and five other hematopoietic malignancies. We determined that Myc-mediated transcriptional repression of the miR-15 and let-7 families in malignant cells was relieved upon HDACi, and Myc was required for their upregulation. The miR-15 and let-7 families then targeted and downregulated the anti-apoptotic genes Bcl-2 and Bcl-xL, respectively, to induce HDACi-mediated apoptosis. Notably, Myc also transcriptionally upregulated these miRNA in untransformed cells, indicating that this Myc-induced miRNA-mediated apoptotic pathway is suppressed in malignant cells, but becomes reactivated upon HDACi. Taken together, our results reveal a previously unknown mechanism by which Myc induces apoptosis independent of the p53 pathway and as a response to HDACi in malignant hematopoietic cells.