Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia
Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia
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DOI：
10.1182/blood-2011-05-351510
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发表时间：
2012-02-02
期刊：
影响因子：
20.3
通讯作者：
Keating, Michael J.
中科院分区：
文献类型：
--
作者：
Sampath, Deepa;Liu, Chaomei;Keating, Michael J.
慢性淋巴细胞白血病（CLL）表现出miR-15 a和miR-16的整体下调以及相关miR-29 b在侵袭性疾病中的选择性沉默。13号染色体[del（13 q14）]的缺失部分解释了miR-15 a和miR-16表达的缺失，但miR-29 b沉默的机制尚不清楚。在本研究中，我们发现组蛋白去乙酰化酶（HDAC）在CLL中过表达，并介导miR-15 a，miR-16和miR-29 b的表观遗传沉默。HDAC抑制触发了转录激活染色质修饰H3 K4 me 2的积累，并在约35%的样品中恢复了miR-15 a、miR-16和miR-29 b的表达。原代CLL细胞中miR-15 a和miR-16的异位表达以及HDAC抑制诱导的miR-15 a、miR-16或miR-29 b的表达与Mcl-1水平下降、线粒体功能障碍和诱导细胞死亡相关，但与Bcl-2无关。因此，我们的研究结果表明HDAC异常沉默CLL中关键肿瘤抑制因子miR-15 a、miR-16和miR-29 b的表达。去乙酰化酶抑制可能是一种治疗策略，恢复这些miR的表达，拮抗Mcl-1，这些细胞中的一种重要的生存蛋白。因此，表现出这种表观遗传沉默的CLL患者可能受益于基于HDAC的疗法。（血。2012;119（5）：1162-1172）
Chronic lymphocytic leukemia (CLL) demonstrates a global down-regulation of miR-15a and miR-16 and a selective silencing of the related miR-29b in aggressive disease. Deletions in chromosome 13 [del(13q14)] partially account for the loss of expression of miR-15a and miR-16, but the mechanisms by which miR-29b becomes silenced is unknown. In the present study, we show that the histone deacetylases (HDACs) are overexpressed in CLL and mediate the epigenetic silencing of miR-15a, miR-16, and miR-29b. HDAC inhibition triggered the accumulation of the transcriptionally activating chromatin modification H3K4me2 and restored the expression of miR-15a, miR-16, and miR-29b in approximately 35% of samples. Ectopic expression of miR-15a and miR-16 and HDAC inhibition-induced expression of miR-15a, miR-16, or miR-29b in primary CLL cells was associated with declines in the levels of Mcl-1, but not Bcl-2, mitochondrial dysfunction, and induction of cell death. Therefore, our results show that HDACs aberrantly silence the expression of the critical tumor suppressors miR-15a, miR-16, and miR-29b in CLL. Deacetylase inhibition may be a therapeutic strategy that restores the expression of these miRs to antagonize Mcl-1, an important survival protein in these cells. Consequently, CLL patients who exhibit such epigenetic silencing may benefit from HDAC inhibitor-based therapy. (Blood. 2012;119(5):1162-1172)