The RPS15-DDX21 complex drives prostate malignancy through transcriptional activation of SCD1.

Development of castration resistance and distant metastasis remain two major clinical challenges in prostate cancer (PCa) treatment. By analyzing multiple public cancer datasets, we found that ribosomal protein S15 (RPS15) is overexpressed in PCa and related to its metastasis. Beyond its canonical role as a structural component of the ribosome, emerging evidence has highlighted the extraribosomal functions of RPS15 in disease progression. Our study demonstrates that RPS15 significantly promotes proliferation and migration in PCa through the establishment of RPS15 knockdown cells and xenograft models. Mechanistically, RPS15 interacts with the functional domain of DExD-box helicase 21 (DDX21) and facilitates the binding of DDX21 to the transcription start region of stearoyl-CoA desaturase-1 (SCD1), thereby enhancing its transcriptional activity and protein expression to drive the growth, ferroptosis-resistance, and metastasis of PCa cells. Moreover, analysis of clinical samples revealed that RPS15, DDX21, and SCD1 are concomitantly upregulated and exhibit strong positive correlations in PCa tissues. Collectively, our findings uncover the significance of the RPS15-DDX21-SCD1 axis in PCa development, expanding the understanding of noncanonical functions of ribosomal proteins and providing new insights for PCa management.