Integrative genomic analysis of OCT1 reveals coordinated regulation of androgen receptor in advanced prostate cancer.

The ligand-dependent transcription factor androgen receptor (AR) plays a critical role in prostate cancer progression. We have previously reported that OCT1, an AR collaborative factor, facilitated the AR genomic bindings to regulate diverse programs of gene expression in AR-dependent prostate cancer cells. Repression of OCT1 binding can serve as a potential treatment strategy for advanced prostate cancer. However, the precise mechanism underlying the functions of OCT1 in advanced prostate cancer, especially the lethal castration-resistant prostate cancer (CRPC) is still unclear. In order to uncover specific OCT1 functions in the disease progression, we explored global OCT1-binding regions by performing chromatin immunoprecipitation sequencing (ChIP-seq) in CRPC model 22Rv1 cells. We found that the OCT1 expression level and the obtained OCT1-binding regions increase in 22Rv1 cells compared with AR-dependent prostate cancer LNCaP cells. Interestingly, microarray analysis revealed that OCT1 regulates CRPC-specific target genes in addition to representative AR-regulated gene such as ACSL3. Pathway analysis showed the importance of OCT1 in regulating cell cycle-related genes. By performing the ChIP assay, we validated ANLN, which is highly expressed in CRPC, and robustly regulated with OCT1 recruitment to the intron and promoter regions in 22Rv1 cells in comparison with LNCaP cells. Furthermore, knockdown of ANLN exhibits impaired cell growth and cell cycle progression, suggesting an important function of ANLN in CRPC cells. In conclusion, these findings raise the possibility that OCT1 coordinates AR signaling in a specific manner that is dependent on disease stage and promotes the progression to CRPC.