Transcriptional activity of c-Jun is critical for the suppression of AR function

• Overexpression of c-Jun efficiently inhibits AR activity.
• The transcriptional activity of c-Jun is important for the AR inhibition.
• c-Jun suppresses AR signaling in hormone-naïve prostate cancer cells and CRPC cells.
• c-Jun may inhibit AR function indirectly through an unknown target gene.

Androgen receptor (AR) signaling plays a pivotal role in growth and survival of prostate cancer cells. c-Jun is an important member of the activator protein 1 (AP-1) family and was shown to interact with AR. However, the role of c-Jun in AR signaling remains controversial, with being a coactivator or a corepressor reported. Here, utilizing multiple approaches, we show that c-Jun efficiently inhibits AR activity and the growth of prostate cancer cells. Overexpression of c-Jun inhibits not only the activities of various androgen-responsive promoters but also the transcripts of multiple AR target genes. Interestingly, long-term c-Jun overexpression also down-regulates AR expression at both the protein and mRNA levels. Molecular analysis suggests that c-Jun inhibits AR transactivation potential via an unknown target gene. The inhibition of AR by c-Jun occurs in both hormone naïve and castration-resistant prostate cancer cells. Our results unravel a novel mechanism by which c-Jun antagonizes the AR signaling.