Abstract
Long non-coding RNAs (lncRNAs) have recently become recognized as crucial players in cancer cellular events including proliferation, migration, and invasion. Herein, we investigated the potential role of lncRNA DLX6-AS1 in prostate cancer cell malignant behaviors and lymph node metastasis. A differentially expressed lncRNA DLX6-AS1 and its downstream regulatory gene (LARGE) were predicted by analysis in silico. RT-qPCR and western blot analysis results demonstrated that DLX6-AS1 was highly expressed, but LARGE was poorly expressed in prostate cancer tissues and cells. The online website indicated that DLX6-AS1 negatively targeted LARGE expression, which was validated by Pearson correlation analysis and MSP. ChIP, RIP, and RNA pull-down assays further suggested that DLX6-AS1 downregulated LARGE expression through recruitment of DNMT1 to its promoter. We induced DLX6-AS1/LARGE overexpression or knockdown to examine their effects through Edu and Transwell assays, which revealed that DLX6-AS1 overexpression accelerated proliferation, invasion, and migration of prostate cancer cells, and that overexpression of LARGE rescued these effects. Tumors xenografts studies confirmed that DLX6-AS1 promoted lymph node metastasis by regulating LARGE, as evidenced by enhanced expression of MMP-9, uPAR, and cathepsin B. In summary, DLX6-AS1 stimulated prostate cancer malignant progression and lymph node metastasis by inducing DNMT1-mediated LARGE methylation, highlighting a potential therapeutic target against prostate cancer.
Highlights
Prostate cancer is the most prevalent malignancy in the male population, ranking in second place as a cause of male cancer-associated death [1]
LncRNAs have already been proved to be abnormally expressed in prostate cancer tissues and are related to the malignant phenotypes of prostate cancer cells, including EMT, metastasis, and invasion [13, 14]
One or more of the abnormally expressed Long non-coding RNAs (lncRNAs) may serve as promising therapeutic targets for treating patients with prostate cancer
Summary
Prostate cancer is the most prevalent malignancy in the male population, ranking in second place as a cause of male cancer-associated death [1]. Lymph node status is a vital prognostic indicator of outcome for prostate cancer [2]. In the past 10 years, great progresses have been made with the advent of new hormonal agents and chemotherapy regimens combined with standard androgen-deprivation therapy for prostate cancer. The application of systemic therapy alone may lead to a castrate-resistant disease state. Additional survival benefits could potentially be achieved with local cytoreductive and/or metastasis-directed therapies [3].
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