The N6-methyladenosine reader IGF2BP3 promotes bladder cancer progression through enhancing HSP90AB1 expression.

Abstract

N⁶-methyladenosine (m⁶A) is the most abundant RNA modification in mammalian cells, and has emerged as an important player in tumour development through post-transcriptional gene regulation. In this study, we found that the m⁶A reader protein IGF2BP3 was the most upregulated m⁶A modifier in bladder cancer through the proteomic analysis of 17 pairs of human bladder cancer tissues and adjacent normal bladder tissues, for which the expression was also positively correlated with higher tumour stage and poorer prognosis. In vitro and in vivo assays demonstrated the powerful oncogenic function of IGF2BP3 in bladder cancer. Further combined analyses of RNA-sequencing, m⁶A-sequencing, and RIP (RNA Binding Protein Immunoprecipitation)-sequencing, as well as site-directed mutagenesis assays and RIP-qPCR identified m⁶A-tagged HSP90AB1 mRNA as a direct target of IGF2BP3. Mechanistically, through in vitro and in vivo assays, as well as clinical sample analysis, we demonstrated that IGF2BP3 modulated the expression of HSP90AB1 in an m⁶A modification-dependent manner, thus activating the PI3K/AKT-signaling pathway, and promoting the development of bladder cancer. Collectively, our study highlights the critical role of the IGF2BP3-HSP90AB1-signaling axis in bladder cancer progression, which may serve as a promising therapeutic approach for bladder cancer.