Involvement of aberrantly activated HOTAIR/EZH2/miR-193a feedback loop in progression of prostate cancer

Abstract

BackgroundThough androgen deprivation therapy is the standard treatment for prostate cancer (PCa), most patients would inevitably progress to castration-resistant prostate cancer (CRPC) which is the main cause of PCa death. Therefore, the identification of novel molecular mechanism regulating cancer progression and achievement of new insight into target therapy would be necessary for improving the benefits of PCa patients. This study aims to study the function and regulatory mechanism of HOTAIR/EZH2/miR-193a feedback loop in PCa progression.MethodsMSKCC and TCGA datasets were used to identify miR-193a expression profile in PCa. Cell Counting Kit-8 (CCK-8) assays, colony formation, invasion, migration, flow cytometry, a xenograft model and Gene Set Enrichment Analysis were used to detect and analyze the biological function of miR-193a. Then, we assessed the role of HOTAIR and EZH2 in regulation of miR-193a expression by using plasmid, lentivirus and small interfering RNA (siRNA). Luciferase reporter assays and chromatin immunoprecipitation assays were performed to detect the transcriptional activation of miR-193a by EZH2 and HOTAIR. Further, qRT-PCR and luciferase reporter assays were conducted to examine the regulatory role of miR-193a controlling the HOTAIR expression in PCa. Finally, the correlation between HOTAIR, EZH2 and miR-193a expression were analyzed using In situ hybridization and immunohistochemistry.ResultsWe found that miR-193a was significantly downregulated in metastatic PCa through mining MSKCC and TCGA datasets. In vitro studies revealed that miR-193a inhibited PCa cell growth, suppressed migration and invasion, and promoted apoptosis; in vivo results demonstrated that overexpression of miR-193a mediated by lentivirus dramatically reduced PCa xenograft tumor growth. Importantly, we found EZH2 coupled with HOTAIR to repress miR-193a expression through trimethylation of H3K27 at miR-193a promoter in PC3 and DU145 cells. Interestingly, further evidence illustrated that miR-193a directly targets HOTAIR showing as significantly reduced HOTAIR level in miR-193a overexpressed cells and tissues. The expression level of miR-193a was inversely associated with that of HOTAIR and EZH2 in PCa.ConclusionThis study firstly demonstrated that miR-193a acted as tumor suppressor in CRPC and the autoregulatory feedback loop of HOTAIR/EZH2/miR-193a served an important mechanism in PCa development. Targeting this aberrantly activated feedback loop may provide a potential therapeutic strategy.Electronic supplementary materialThe online version of this article (doi: 10.1186/s13046-017-0629-7) contains supplementary material, which is available to authorized users.

LINC00511 exacerbated T-cell acute lymphoblastic leukemia via miR-195-5p/LRRK1 axis

“…LncRNA PVT1 was identified to modulate chondrocyte apoptosis in osteoarthritis by decreasing miR-488-3p expression [29]. The up-regulated HOTAIR promotes cell proliferation of prostate cancer cells [30]. Present study uncovered that LINC00511 was up-regulated in T-ALL bloods (or cells) compared with normal bloods (or PBMC).…”

HOTAIR: An Oncogenic Long Non-Coding RNA in Human Cancer

“…In addition, miR-193a acted as a tumor suppressor, inhibiting growth, migration and invasion in CRPC cells via the regulatory feedback loop of HOTAIR/ EZH2/miR-193a. Thus targeting this aberrantly activated loop could provide a potential therapeutic strategy in PCs [58]. Polyphyllin I (PPI), one of the steroidal saponins in Paris polyphylla, reportedly exhibited antitumor activities.…”

Downregulation of long non-coding RNA nuclear enriched abundant transcript 1 promotes cell proliferation and inhibits cell apoptosis by targeting miR-193a in myocardial ischemia/reperfusion injury

“…In addition, only the rat cardiac muscle cell line H9c2 was available for this study due to the scarcity in diversity of myocardial cells in China, which resulted in the lack of verification in other cell lines, and similar limitations could be observed in some previous studies that focus on myocardial ischemia/reperfusion (I/R) injury [25,26]. , which is embedded in a CpG island, has been identified as a tumor suppressive miRNA in several cancers such as oral carcinoma, lung cancer and colorectal cancer [27][28][29][30][31][32][33]. Apart from cancers, it is disclosed that miR-193a is downregulated in intestinal inflammation in colitis, and upregulation of miR-193a promotes anti-inflammatory activities via targeting apoptotic pathways death receptor-6 (DR6) [34].…”