Abstract
ObjectiveGenistein is a soy isoflavone that has antitumor activity both in vitro and in vivo. It has been shown that genistein inhibits many type of cancers including prostate cancer (PCa) by regulating several cell signaling pathways and microRNAs (miRNAs). Recent studies suggest that the long non-coding RNAs (lncRNAs) are also involved in many cellular processes. At present there are no reports about the relationship between gensitein, miRNAs and lncRNAs. In this study, we focused on miRNAs, lncRNA that are regulated by genistein and investigated their functional role in PCa.MethodMicroarray (SurePrint G3 Human GE 8×60K) was used for expression profiling of genistein treated and control PCa cells (PC3 and DU145). Functional assay (cell proliferation, migration, invasion, apoptosis and cell cycle assays) were performed with the PCa cell lines, PC3 and DU145. Both in vitro and in vivo (nude mouse) models were used for growth assays. Luciferase reporter assays were used for binding of miR-34a to HOTAIR.ResultsLncRNA profiling showed that HOTAIR was highly regulated by genistein and its expression was higher in castration-resistant PCa cell lines than in normal prostate cells. Knockdown (siRNA) of HOTAIR decreased PCa cell proliferation, migration and invasion and induced apoptosis and cell cycle arrest. miR-34a was also up-regulated by genistein and may directly target HOTAIR in both PC3 and DU145 PCa cells.ConclusionsOur results indicated that genistein inhibited PCa cell growth through down-regulation of oncogenic HOTAIR that is also targeted by tumor suppressor miR-34a. These findings enhance understanding of how genistein regulates lncRNA HOTAIR and miR-34a in PCa.
Highlights
LncRNA profiling showed that HOX transcript antisense RNA (HOTAIR) was highly regulated by genistein and its expression was higher in castration-resistant prostate cancer (PCa) cell lines than in normal prostate cells
Knockdown of HOTAIR decreased PCa cell proliferation, migration and invasion and induced apoptosis and cell cycle arrest. miR-34a was up-regulated by genistein and may directly target HOTAIR in both PC3 and DU145 PCa cells
Our results indicated that genistein inhibited PCa cell growth through down-regulation of oncogenic HOTAIR that is targeted by tumor suppressor miR-34a
Summary
It has been reported that genistein increased expression of tumor suppressor miR-146a, causing inhibition of the EGFR and NF-kB pathway [13,14]. MiR-27a has been reported to be a oncogenic miRNA regulated by genistein and regulates VEGF signaling by targeting ZBTB10 [15,16]. Our previous studies showed that genistein treatment significantly down-regulated the expression of oncogenic miR-151 which directly targets SOX17 and ARHGDIA [17]. SOX17 was reported to be a tumor suppressor gene that inhibits WNT/b-catenin signaling by targeting both b-catenin and T-cell factor (TCF)/lymphoid enhancer factor (LEF) proteins [18,19,20]. ARHGDIA negatively regulates the Rho family of GTPases (Rho, Rac, and Cdc42) [21] that are involved in the WNT signaling pathway [22]. We found that genistein down-regulates the RAC1 and EP300 genes that are important regulators of VEGF-mediated angiogenesis [23,24] and the EGFR gene by up-regulating miR-574-3p [25]
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