Simple SummaryThis is the first study that has investigate the potential role of theSRRTgene in prostate cancer using clinical samples. We found that high expression of SRRT was significantly associated with poor overall and cause-specific survival. High SRRT expression was also significantly associated with high Gleason score, PSA abundance, pathological T category, and common genomic aberrations in PCa such asPTENloss,ERGgain, mutantTP53, orATM. Gene set enrichment analysis suggested that SRRT may play a role in regulating the expression of genes contributing to prostate cancer aggressiveness. Our findings suggest that SRRT could be a prognostic and diagnostic biomarker for lethal PCa, as well as a potential therapeutic target.AbstractArsenite-resistance protein 2, also known as serrate RNA effector molecule (ARS2/SRRT), is known to be involved in cellular proliferation and tumorigenicity. However, its role in prostate cancer (PCa) has not yet been established. We investigated the potential role of SRRT in 496 prostate samples including benign, incidental, advanced, and castrate-resistant patients treated by androgen deprivation therapy (ADT). We also explored the association of SRRT with common genetic aberrations in lethal PCa using immunohistochemistry (IHC) and performed a detailed analysis of SRRT expression using The Cancer Genome Atlas (TCGA PRAD) by utilizing RNA-seq, clinical information (pathological T category and pathological Gleason score). Our findings indicated that high SRRT expression was significantly associated with poor overall survival (OS) and cause-specific survival (CSS). SRRT expression was also significantly associated with common genomic aberrations in lethal PCa such as PTEN loss, ERG gain, mutant TP53, or ATM. Furthermore, TCGA PRAD data revealed that high SRRT mRNA expression was significantly associated with higher Gleason scores, PSA levels, and T pathological categories. Gene set enrichment analysis (GSEA) of RNAseq data from the TCGA PRAD cohort indicated thatSRRTmay play a potential role in regulating the expression of genes involved in prostate cancer aggressiveness. Conclusion: The current data identify the SRRT’s potential role as a prognostic for lethal PCa, and further research is required to investigate its potential as a therapeutic target.