Global epigenetic regulation of microRNAs in multiple myeloma.
Global epigenetic regulation of microRNAs in multiple myeloma.
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DOI：
10.1371/journal.pone.0110973
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ghobrial IM
中科院分区：
文献类型：
--
作者：
Zhang W;Wang YE;Zhang Y;Leleu X;Reagan M;Zhang Y;Mishima Y;Glavey S;Manier S;Sacco A;Jiang B;Roccaro AM;Ghobrial IM
表观遗传学改变经常发生在肿瘤发生过程中，DNA高甲基化可能是肿瘤细胞中抑癌基因失活的原因。对多发性骨髓瘤(MM)的研究表明，在临床侵袭性亚型中，DNA甲基化模式多种多样，局部高甲基化改变。我们研究了复发/难治性多发性骨髓瘤患者的整体甲基化模式，发现大多数甲基化峰值位于多发性骨髓瘤样本的内含子和基因内区。因此，我们研究了甲基化对MM中miRNA调控的影响。到目前为止，MM中发生全局miRNA抑制的机制尚未完全描述。在这项研究中，我们报告了多发性骨髓瘤中miRNAs的超甲基化，并在DNA去甲基化试剂5-氮杂-2‘-脱氧胞苷存在或不存在的情况下，使用亚硫酸氢盐测序和甲基化特异性聚合酶链式反应(MSP)在多发性骨髓瘤细胞系中进行确认。我们进一步表征了miR-152、-10b-5p和-34c-3p的高甲基化抑制作用，这被证明在MM患者中与健康人相比下调，以及miR-152-、-10b-5p和miR-34c-3p预测的靶基因的丰富，如在原代MM细胞的mRNA水平上所示。这些特定的miRNAs去甲基化或获得功能研究导致这些miRNAs诱导细胞凋亡和抑制增殖，并下调这些miRNAs可能的癌基因靶点，如DNMT1，E2F3，BTRC和MYCBP。这些发现为MM亚群的表观遗传治疗方法提供了理论基础。
Epigenetic changes frequently occur during tumorigenesis and DNA hypermethylation may account for the inactivation of tumor suppressor genes in cancer cells. Studies in Multiple Myeloma (MM) have shown variable DNA methylation patterns with focal hypermethylation changes in clinically aggressive subtypes. We studied global methylation patterns in patients with relapsed/refractory MM and found that the majority of methylation peaks were located in the intronic and intragenic regions in MM samples. Therefore, we investigated the effect of methylation on miRNA regulation in MM. To date, the mechanism by which global miRNA suppression occurs in MM has not been fully described. In this study, we report hypermethylation of miRNAs in MM and perform confirmation in MM cell lines using bisulfite sequencing and methylation-specific PCR (MSP) in the presence or absence of the DNA demethylating agent 5-aza-2′-deoxycytidine. We further characterized the hypermethylation-dependent inhibition of miR-152, -10b-5p and -34c-3p which was shown to exert a putative tumor suppressive role in MM. These findings were corroborated by the demonstration that the same miRNAs were down-regulated in MM patients compared to healthy individuals, alongside enrichment of miR-152-, -10b-5p, and miR-34c-3p-predicted targets, as shown at the mRNA level in primary MM cells. Demethylation or gain of function studies of these specific miRNAs led to induction of apoptosis and inhibition of proliferation as well as down-regulation of putative oncogene targets of these miRNAs such as DNMT1, E2F3, BTRC and MYCBP. These findings provide the rationale for epigenetic therapeutic approaches in subgroups of MM.
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影响因子：
64.8
作者：
Lu, J;Getz, G;Golub, TR
通讯作者：
Golub, TR
影响因子：
9
作者：
通讯作者：
--
影响因子：
20.3
作者：
Martinez-Garcia, Eva;Popovic, Relja;Licht, Jonathan D.
通讯作者：
Licht, Jonathan D.
影响因子：
5.7
作者：
Hiroki, Eri;Akahira, Jun-ichi;Yaegashi, Nobuo
通讯作者：
Yaegashi, Nobuo
影响因子：
20.3
作者：
Kaiser, Martin F.;Johnson, David C.;Morgan, Gareth J.
通讯作者：
Morgan, Gareth J.