LncRNA ZNF503-AS1 acts as a tumor suppressor in bladder cancer by up-regulating Ca2+ concentration via transcription factor GATA6

Ca2+ homeostasis plays a pivotal role in regulating proliferation and apoptosis during cancer development. This study intended to examine the potential tumor-suppressing role of ZNF503 antisense RNA 1 (ZNF503-AS1) in bladder cancer, which may be implicated in the regulation of Ca2+ homeostasis. Differentially expressed long non-coding RNAs (lncRNAs) related to bladder cancer were identified using microarray analysis, followed by the verification of transcription factors to which they bind. The relationship between ZNF503-AS1, GATA6 and SLC8A1 was assessed using dual luciferase reporter, RIP and ChIP assays. The expression levels of ZNF503-AS1, GATA6 and SLC8A1 were modulated to examine their effects on the tumorigenic potential, intracellular Ca2+ concentration and Ca2+-ATPase activity in bladder cancer cells. The in vivo tumorigenic ability was validated in nude mice. Microarray-based expression profile analysis of the GEO GSE61615 dataset revealed that the expression of ZNF503-AS1 was decreased in bladder cancer. Subsequently, we found that ZNF503-AS1 can bind to the transcription factor GATA6 to up-regulate the expression of SLC8A1. ZNF503-AS1 and SLC8A1 were found to be down-regulated in both primary bladder cancer tissues and cells. Exogenous overexpression of ZNF503-AS1 or SLC8A1 attenuated bladder cancer cell proliferation, invasion and migration, but promoted their apoptosis, accompanied by decreased Ca2+-ATPase activities and increased intracellular Ca2+ concentrations. Additional in vivo experiments validated the inhibitory effect of ZNF503-AS1 overexpression on the tumorigenic capacity of bladder cancer cells in nude mice. ZNF503-AS1 can recruit transcription factor GATA6 to up-regulate SLC8A1 expression, thereby increasing the intracellular Ca2+ concentration and repressing the proliferation, invasion and migration, and enhancing the apoptosis of bladder cancer cells.