CircAKT3 promotes prostate cancer proliferation and metastasis by enhancing the binding of RPS27A and RPL11.

BACKGROUND

Metastatic prostate cancer (PCa) is a leading cause of mortality among PCa patients. Although circular RNAs (circRNAs) are recognized for their pivotal roles in tumorigenesis, the specifics of their influence within the context of PCa have yet to be fully elucidated.

METHODS

RT-qPCR was conducted to evaluate circAKT3 expression in PCa cells and in both tumor and adjacent noncancerous tissues. The oncogenic role of circAKT3 was confirmed through a combination of in vitro and in vivo experiments. Mechanistic investigations using RNA-pulldown, RNA immunoprecipitation (RIP), fluorescence in situ hybridization (FISH), immunofluorescence (IF), and Chromatin Immunoprecipitation (ChIP) assays explored how circAKT3 modulates c-Myc activity via interactions with RPS27A and RPL11. Additionally, Western Blotting and further in vitro and in vivo studies assessed circAKT3's influence on PCa progression through MST1.

RESULTS

This research identified the function and regulation of circAKT3, a circRNA derived from exons 2 to 8 of the kinase-b3 (AKT3) gene, in human PCa cells. CircAKT3 was significantly correlated with clinical indicators of disease severity, including D'Amico risk classification, the Gleason score, and pT stage. Both in vitro and in vivo experiments demonstrated that circAKT3 knockdown inhibited PCa cell proliferation, migration, and invasion. Lipid nanoparticles encapsulating si-circAKT3 (LNP-si-circAKT3) effectively suppressed the growth of bone tumors formed by PCa cells. Mechanistically, circAKT3 acted as a protein scaffold between ribosomal protein S27a (RPS27A) and ribosomal protein L11 (RPL11), promoting their cytoplasmic translocation and reducing nuclear RPL11 levels, ultimately diminishing RPL11's interaction with c-Myc and resulting in enhanced c-Myc-driven suppression of macrophage stimulating 1 (MST1) expression. Consequently, the decreased MST1 led to PCa progression and metastasis. CircAKT3 formation was facilitated by both flanking Alu elements and the RNA binding protein Quaking (QKI). Additionally, downregulation of the RNA helicase URH49 resulted in the nuclear accumulation of circAKT3, finally suppressing MST1 expression.

CONCLUSION

Our findings suggest that circAKT3 acts as a protein scaffold, promoting the interaction between RPS27A and RPL11, thereby influencing c-Myc activity and PCa progression. This study underscores the crucial role of circAKT3 in PCa and its potential as a therapeutic target to impede malignancy progression and metastasis.