Anti-cancer effect of LINC00478 in bladder cancer correlates with KDM1A-dependent MMP9 demethylation

Abstract

Abstract Accumulating evidence has highlighted the important roles of long intergenic non-coding RNAs (lincRNAs) during cancer progression. However, the involvement of LINC00478 in bladder cancer remains largely unclear. Accordingly, the current study sought to investigate the function of LINC00478 on malignant phenotypes of bladder cancer cells as well as the underlying mechanism. By integrating data from in silico analysis, we uncovered that LINC00478 was differentially expressed in bladder cancer. We further analyzed the expression of LINC00478 and matrix metalloprotein 9 (MMP9) in bladder cancer tissues and cell lines and observed a significant decline in LINC00478 expression and an elevation in MMP9 expression. In addition, chromatin immunoprecipitation, RNA-binding protein immunoprecipitation, and RNA pull-down assays predicted and validated that LINC00478 targeted lysine-specific demethylase-1 (KDM1A) and down-regulated the expression of MMP9 by decreasing the monomethylation on lysine 4 of histone H3 (H3K4me1) of MMP9 promoter. Treatment with KDM1A inhibitor tranylcypromine (TCP) also led to an increase in the enrichment of H3K4me1 in the MMP9 promoter region. Through gain- and loss-of-function approaches, we found that LINC00478 up-regulation diminished the malignant phenotype of bladder cancer cells in vitro, and further inhibited xenograft tumor growth and metastasis in vivo by repressing MMP9. Collectively, our findings unraveled a LINC00478-mediated inhibitory mechanism in bladder cancer via the recruitment of histone demethylation transferase KDM1A to the MMP9 promoter region, which can provide potential implications for novel therapeutic targets against bladder cancer.