MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1
MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1
复制标题
DOI：
10.1182/blood-2008-07-170589
复制
发表时间：
2009-06-18
期刊：
影响因子：
20.3
通讯作者：
Marcucci, Guido
中科院分区：
文献类型：
--
作者：
Garzon, Ramiro;Liu, Shujun;Marcucci, Guido
异常的 DNA 高甲基化通过沉默参与造血的结构正常基因而导致骨髓性白血病的发生。 MicroRNA (miRNA) 是非编码 RNA，通过靶向蛋白质编码 mRNA 来调节基因表达。最近，miRNA 已被证明在恶性细胞的基因高甲基化和沉默中发挥着靶点和效应器的作用。在当前的研究中，我们发现急性髓系白血病细胞中miR-29b的强制表达导致DNA甲基转移酶DNMT1、DNMT3A和DNMT3B在RNA和蛋白质水平上的表达显着减少。这反过来又导致整体 DNA 甲基化减少，并通过启动子 DNA 低甲基化重新表达 p15(INK4b) 和 ESR1。尽管 DNMT3A 和 DNMT3B 的下调是 miR-29b 与这些基因的 3' 非翻译区直接相互作用的结果，但在 DNMT1 3' 非翻译区中没有发现预测的 miR-29b 相互作用位点。进一步的实验表明，miR-29b 通过靶向 DNMT1 基因的反式激活因子 Sp1 来间接下调 DNMT1。总而言之，这些数据提供了急性髓性白血病中 miRNA 与异常 DNA 高甲基化之间的新功能联系，并表明合成 miR-29b 寡核苷酸作为有效的低甲基化化合物的潜在治疗用途。 （血。2009；113：6411-6418）
Aberrant DNA hypermethylation contributes to myeloid leukemogenesis by silencing structurally normal genes involved in hematopoiesis. MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression by targeting protein-coding mRNAs. Recently, miRNAs have been shown to play a role as both targets and effectors in gene hypermethylation and silencing in malignant cells. In the current study, we showed that enforced expression of miR-29b in acute myeloid leukemia cells resulted in marked reduction of the expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B at both RNA and protein levels. This in turn led to decrease in global DNA methylation and reexpression of p15(INK4b) and ESR1 via promoter DNA hypomethylation. Although down-regulation of DNMT3A and DNMT3B was the result of a direct interaction of miR-29b with the 3' untranslated regions of these genes, no predicted miR-29b interaction sites were found in the DNMT1 3' untranslated regions. Further experiments revealed that miR-29b down-regulates DNMT1 indirectly by targeting Sp1, a transactivator of the DNMT1 gene. Altogether, these data provide novel functional links between miRNAs and aberrant DNA hypermethylation in acute myeloid leukemia and suggest a potentially therapeutic use of synthetic miR-29b oligonucleotides as effective hypomethylating compounds. (Blood. 2009; 113: 6411-6418)