CircXRN2 suppresses tumor progression and glycolysis in human bladder cancer through activating the Hippo signaling pathway

Abstract Background Bladder cancer (BCa) is the fourth most common malignant tumor with a poor prognosis worldwide. Further exploration and research are needed for unmasking the underlying roles and molecular mechanism of circular RNAs. In the current study, our findings showed that circXRN2 suppresses tumor progression and glycolysis in human bladder cancer through activating the Hippo signaling pathway. Methods RNA immunoprecipitation (RIP) followed by circRNA sequencing confirmed circXRN2 as the research object. Overexpression of circXRN2 and knockdown of TAZ/YAP further verified the biological functions in T24 and TCCSUP. RIP, immunoprecipitation and co-immunoprecipitation were used to elucidate the interaction between circXRN2 and LATS1. Chromatin immunoprecipitation (ChIP) and luciferase reporter experiment were employed to ensure the regulatory roles of the Hippo pathway in transcriptional activity. Seahorse metabolic analyzer was used to evaluate glycolytic rate. Results CircXRN2 is aberrantly downregulated in bladder cancer tissues and cell lines. CircXRN2 inhibits proliferation and migration of tumor cells both in vitro and in vivo. Besides, circXRN2 serves as a negative regulator in glycolytic metabolism. Mechanically, circXRN2 prevents LATS1 from SPOP-mediated degradation by binding to the SPOP-related degron and then activates the Hippo signaling pathway to exert various biological functions. CircXRN2-LATS1-Hippo regulatory axis modulates cell proliferation, migration and glucose metabolism in human bladder cancer. Conclusions CircXRN2 suppresses tumor progression and glycolysis in human bladder cancer through activating the Hippo signaling pathway. Our results indicated novel therapeutic targets and provided promising strategies for clinical intervention in human bladder cancer.