LncRNA ZNF503-AS1 acts as a tumor suppressor in bladder cancer by up-regulating Ca 2+ concentration via transcription fa
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ORIGINAL PAPER
LncRNA ZNF503-AS1 acts as a tumor suppressor in bladder cancer by up-regulating Ca2+ concentration via transcription factor GATA6 Haiqing He 1 & Shuiqing Wu 1 & Kai Ai 1 & Ran Xu 1 & Zhaohui Zhong 1 & Yinhuai Wang 1 & Lei Zhang 1 & Xiaokun Zhao 1 & Xuan Zhu 1 Accepted: 17 September 2020 # International Society for Cellular Oncology 2020
Abstract Purpose 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. Methods 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 ZNF503AS1, 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. Results Microarray-based expression profile analysis of the GEO GSE61615 dataset revealed that the expression of ZNF503AS1 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. Conclusion 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. Keywords Bladder cancer . ZNF503-AS1 . LncRNA . Transcription factor . GATA6 . SLC8A1 . Proliferation . Invasion and migration . Ca2+ concentration
1 Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13402-020-00563-z) contains supplementary material, which is available to authorized users. * Xiaokun Zhao [email protected] * Xuan Zhu [email protected] 1
Department of Urology, The Second Xiangya Hospital, Central South University, No.139 Renmin Road, Changsha 410011, Hunan Province, People’s Republic of China
Bladder cancer is regarded as a heterogeneous disease, with up to 30% of the cases exhibiting muscle-invasive characteristics accompanied by a high risk of distant metastasis, wh
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