AATF is Overexpressed in Human Bladder Cancer and Regulates Chemo-Sensitivity Through Survivin

Objective: Dysregulation of apoptosis antagonizing transcription factor (AATF) has been reported to be closely associated with human cancers. However, its involvement in human bladder cancer (BC) remains unexplored. This study aimed to investigate the clinical significance and biological roles of AATF in human bladder cancers. Methods: AATF protein expression was examined in 107 cases of bladder cancer tissues using immunohistochemistry. AATF plasmid transfection and small interfering RNA (siRNA) knockdown were performed in T24 and 5637 cell lines. CCK-8, colony formation, annexin V/PI, JC-1 staining, and Western blotting were carried out to investigate the biological roles and underlying mechanisms of AATF in bladder cancer cells. Results: Our results showed that AATF expression was upregulated in human bladder cancer specimens and correlated with T stage. Analysis of the Oncomine database showed elevation of AATF mRNA in BC tissues. The Cancer Genome Atlas (TCGA) data suggested that high AATF expression correlated with poor patient survival. Western blotting showed that AATF protein expression was higher in BC cell lines compared to normal bladder transitional epithelial cell line SV-HUC-1. CCK-8 and colony assays showed that ectopic AATF expression upregulated cell growth rate and colony numbers. CCK-8, annexin V/ propidium iodide (PI), JC-1 assays and Western blotting showed that AATF overexpression decreased cisplatin sensitivity, downregulated cisplatin-induced apoptosis and upregulated mitochondrial membrane potential, with decreased cytochrome c and cleaved-PARP expression. AATF siRNA knockdown showed the opposite effects. Mechanistically, AATF over expression upregulated cyclin E and Survivin at both mRNA and protein levels. The decreased cisplatin sensitivity/apoptosis induced by ectopic AATF were reversed after treatment with Survivin inhibitor YM155. Conclusion: Our results showed that AATF was overexpressed in human bladder cancers and promoted malignant behavior by regulating cyclin E and Survivin, indicating AATF could serve as a malignant biomarker and potential therapeutic target in BC.