Pirin: a potential novel therapeutic target for castration‐resistant prostate cancer regulated by miR‐455‐5p

Androgen deprivation therapy is frequently used to treat prostate cancer ( PC a), but resistance can occur, a condition known as castration‐resistant prostate cancer ( CRPC ). Thus, novel approaches for identification of CRPC are important for designing effective PC a treatments. Analysis of micro RNA (mi RNA ) expression signatures by RNA sequencing showed that both passenger and guide strands of the miR‐455 ‐duplex ( miR‐455‐5p and miR‐455‐3p , respectively) acted as antitumor mi RNA s in PC a cells. The involvement of mi RNA passenger strands in cancer pathogenesis is a novel concept for mi RNA functionality. Based on a large patient cohort in The Cancer Genome Atlas, expression of eight miR‐455‐5p/‐3p target genes ( PIR : P  =   0.0137, LRP 8 : P  =   0.0495, IGFBP 3 : P  =   0.0172, DMBX 1 : P  =   0.0175 , CCDC 64 : P  =   0.0446, TUBB 1 : P  =   0.0149, KIF 21B : P  =   0.0336, and NFAM 1 : P  =   0.0013) was significantly associated with poor prognosis of PC a patients. Here, we focused on PIR (pirin), a highly conserved member of the cupin superfamily. PIR expression was directly regulated by miR‐455‐5p , and PIR overexpression was detected in hormone‐sensitive prostate cancer ( HSPC ) surgical specimens and CRPC autopsy specimens. Loss‐of‐function assays using si RNA or an inhibitor (bisamide) showed that downregulation of PIR expression blocked cancer cell migration and invasion. Moreover, the miR‐455‐5p / PIR axis contributed to cancer cell aggressiveness. These results suggest that PIR might be a promising diagnostic marker for HSPC and CRPC . Furthermore, CRPC treatment strategies targeting PIR may be possible in the future. Identification of antitumor mi RNA s, including mi RNA passenger strands, may contribute to the development of new diagnostic markers and therapeutic strategies for CRPC .