Engineered targeting OIP5 sensitizes bladder cancer to chemotherapy resistance via TRIP12-PPP1CB-YBX1 axis

In this project we identify OIP5 as a novel chemoresistance associated gene. OIP5 expression is upregulated in GEM,DDP resistant bladder cancer cell lines, organoids, and clinical specimens, and stratification of the bladder cancer cohort in The Cancer Genome Atlas database showed that high OPI5 expression was associated with poor prognosis. Mechanistically, we determined that GEM, DDP therapy induces NFkB signaling, which promotes p65 mediated transcriptional activation of OIP5. OIP5 recruits the E3 ubiquitin ligase TRIP12 to bind to and degrade the phosphatase PPP1CB, thereby enhancing the transcription factor activity of YBX1. This in turn upregulates drug resistance related genes under the transcriptional control of YBX1, leading to chemoresistance. Furthermore, PPP1CB degradation can enhance the phosphorylation activity of IKK, triggering the NFkB signaling cascade, which further stimulates OIP5 gene expression, thus forming a negative feedback regulatory loop.