Long Noncoding RNA DGUOK-AS1 Promotes Bladder Cancer Progression by Enhancing EFTUD2 Stability

Long noncoding RNAs (lncRNAs) are increasingly being recognized to play important roles in cancer pathogenesis. However, the functional mechanisms of most lncRNAs remain poorly understood.

RNA sequencing was performed to identify differentially expressed lncRNAs between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). In vitro and in vivo assays were conducted to investigate the functional role of lncRNA deoxyguanosine kinase 1 antisense RNA 1 (DGUOK-AS1). Meanwhile, RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, Western blot, and reverse transcription quantitative polymerase chain reaction assays were performed to explore the potential regulatory mechanisms of DGUOK-AS1 on its target genes.

Our analysis revealed a significant upregulation of lncRNA DGUOK-AS1 in MIBC compared with NMIBC. Functionally, DGUOK-AS1 was found to enhance the proliferation and invasion of bladder cancer (BC) cells by interacting with elongation factor Tu GTP binding domain containing 2 (EFTUD2), a 116-kDa U5 small nuclear ribonucleoprotein component. Mechanistically, DGUOK-AS1 directly binds to EFTUD2 and the deubiquitinating protein valosin-containing protein-interacting protein 1, thereby shielding EFTUD2 from ubiquitination and subsequent degradation. Furthermore, EFTUD2 orchestrates the exclusion of cassette exon 11 from macrophage-stimulating 1 receptor, leading to the production of the RONΔ165 isoform. This isoform activates the Akt/protein kinase B signaling pathway, which is crucial for cancer progression.

DGUOK-AS1 drives BC progression via the EFTUD2/MST1R/Akt axis, offering a promising therapeutic target for BC treatment.