Hypermethylation of miRNA-589 promoter leads to upregulation of HDAC5 which promotes malignancy in non-small cell lung cancer
Hypermethylation of miRNA-589 promoter leads to upregulation of HDAC5 which promotes malignancy in non-small cell lung cancer
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DOI：
10.3892/ijo.2017.3967
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发表时间：
2017-06-01
影响因子：
5.2
通讯作者：
Chang, Dongmin
中科院分区：
文献类型：
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作者：
Liu, Changhong;Lv, Desheng;Chang, Dongmin
组蛋白脱乙酰酶（HDAC）对于调节染色质活性至关重要，染色质活性在各种癌症的细胞增殖、分化和凋亡中起关键作用。因此，HDAC抑制剂已被用作癌症治疗的有效治疗剂。然而，组蛋白去乙酰化酶在肺癌中的表达谱和调控机制尚不清楚。在本研究中，在非小细胞肺癌（NSCLC）中观察到异常高水平的HDAC 5，进一步分析表明NSCLC标本中HDAC 5与肿瘤抑制因子miR-589- 5 p之间存在负相关。因此，miR-589- 5 p通过靶向NSCLC细胞中HDAC 5 mRNA的3 'UTR来降低HDAC 5的表达。考虑到NSCLC中miR-589- 5 p的丢失，检查了miR-589基因启动子的甲基化状态。与肺上皮细胞相比，NSCLC细胞中miR-589基因启动子的超甲基化更为显著，5-氮杂-2-脱氧胞苷（5-Aza-dC）抑制甲基化可降低HDAC 5的表达。此外，本研究还对HDAC 5的几个下游基因簇进行了研究。因此，发现miR-589- 5 p/HDAC 5通路在NSCLC细胞中调节许多细胞周期和上皮-间质转化（EMT）相关基因。体外和体内表型实验揭示了miR-589- 5 p/HDAC 5通路在NSCLC细胞的迁移、侵袭和致瘤性中的关键作用。这些发现证明了NSCLC中HDAC 5失调的新机制，并表明miR-589- 5 p/HDAC 5通路可能代表了NSCLC的新预后生物标志物和治疗靶点。
Histone deacetylases (HDACs) are crucial for regulating chromatin activity, which plays a critical role in cell proliferation, differentiation, and apoptosis of various cancers. Therefore, HDAC inhibitors have been applied as effective therapeutic agents for cancer treatment. However, the expression profiles and regulatory mechanisms of histone deacetylases in lung cancer are not well understood. In the present study, aberrant high levels of HDAC5 were observed in non-small cell lung cancer (NSCLC) and further analysis indicated a negative relationship between HDAC5 and a tumor suppressor, miR-589-5p, in NSCLC specimens. Consistently, miR-589-5p reduced the expression of HDAC5 by targeting the 3'UTR of HDAC5 mRNA in NSCLC cells. Considering the loss of miR-589-5p in NSCLC, the methylation status of the miR-589 gene promoter was examined. The hypermethylation of the miR-589 gene promoter was more significant in NSCLC cells compared with lung epithelial cells, and methylation inhibition by 5-aza-2-deoxycytidine (5-Aza-dC) decreased HDAC5 expression. Furthermore, several downstream gene clusters of HDAC5 were studied in the present investigation. As a result, miR-589-5p/HDAC5 pathway was found to regulate a number of cell cycle and epithelial-mesenchymal transition (EMT)-related genes in NSCLC cells. In vitro and in vivo phenotype experiments revealed a critical role of miR-589-5p/HDAC5 pathway in the migration, invasion, and tumorigenicity of NSCLC cells. These findings demonstrate a novel mechanism for deregulation of HDAC5 in NSCLC and suggest that miR-589-5p/HDAC5 pathway may represent a new prognostic biomarker and therapeutic target against NSCLC.