Hypermethylation of miRNA-589 promoter leads to upregulation of HDAC5 which promotes malignancy in non-small cell lung cancer
| Autor: | Dongmin Chang, Mo Li, Ge Sun, Xuefei Zhang, Yu Bai, Desheng Lv, Changhong Liu |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Cancer Research Epithelial-Mesenchymal Transition Carcinogenesis Decitabine Histone Deacetylases Mice 03 medical and health sciences 0302 clinical medicine Carcinoma Non-Small-Cell Lung Cell Line Tumor microRNA medicine Animals Humans Neoplasm Invasiveness Promoter Regions Genetic Lung cancer Aged Cell Proliferation Histone deacetylase 5 Oncogene biology Cancer DNA Methylation Middle Aged Cell cycle medicine.disease Xenograft Model Antitumor Assays respiratory tract diseases Gene Expression Regulation Neoplastic Histone Deacetylase Inhibitors MicroRNAs 030104 developmental biology Histone Oncology 030220 oncology & carcinogenesis DNA methylation Azacitidine biology.protein Cancer research Female |
| Zdroj: | International Journal of Oncology. 50:2079-2090 |
| ISSN: | 1791-2423 1019-6439 |
| DOI: | 10.3892/ijo.2017.3967 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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