The lncRNA-PCAT-6 Enhances Prostate Cancer Cell Invasion via Altering TR4 Nuclear Receptor-Mediated Tumor Suppressor KISS-1 Expression

Abstract

Background: While the TR4 nuclear receptor may play important roles to impact the prostate cancer (PCa) progression, its relation to lncRNAs to impact PCa cell invasion, remains unclear. Here we found the lncRNA-PCAT-6 might function via increasing TR4 transactivation to increase the PCa cell invasion. Methods: C4-2 and CWR22Rv-1 cells were used for the study. Lentiviral system was used for ectopic expression or knockdown of gene expressions. RNA extraction and quantitative Real-Time PCR were applied to determine the mRNA levels. Matrigel transwell Invasion Assays were used to test the invasiveness of PCa cells. Chromatin Immunoprecipitation assay (ChIP) was applied to detect the protein- gene promoter (genomic DNA) binding. TR4 pull-down assay was used to detect the interaction and function regulation between protein and non-coding RNAs. Results: Further studies revealed that adding lncRNA-PCAT-6 could increase TR4-promoted PCa cell invasion via modulating the tumor suppressor KISS-1 expression, and altering KISS-1 expression could partially reverse/block the TR4-enhanced PCa cell invasion in CWR22Rv1 and C4-2 cells. Mechanism dissection revealed that lncRNA-PCAT-6 could increase TR4 transactivation, which could then suppress KISS-1 expression via transcriptional regulation through direct binding to TR4-response-elements (TR4REs) on the 5'-promoter region. Human clinical sample surveys also revealed that TR4, lncRNA-PCAT6, and KISS-1 play critical roles in PCa cell invasion and patients overall survival rates. Conclusions: Our results suggest that targeting this newly identified lncRNA-PCAT-6/TR4/KISS-1 signaling with the small molecule, lncRNA-PCAT-6-shRNA, may help in the development of a more potent therapeutic approach to better suppress PCa metastases. Funding Statement: This study was supported by George Whipple Professorship Endowment, the Taiwan Department of Health Clinical Trial Research Center of Excellence (MOHW105-TDU-B-212-133019 to China Medical University, Taichung, Taiwan), Science and Technology Planning Project of Guangzhou (No.201804010087 and No.201904010035) and Natural Science Foundation of Guangdong Province (No. 2018A030313905). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This study was in accordance with Helsinki Declaration and approved by the Medical Ethics Committee of the University of Rochester.