Abstract 941: Suppression of the androgen receptor function by c-Jun in prostate cancer via a dual mechanism

Abstract

Abstract Androgen receptor (AR) signaling plays a pivotal role in growth and survival of prostate cancer cells. Upon ligand binding, AR translocates into the nucleus and regulates expression of multiple genes through binding their promoter regions. Thus, altered expression and activity of AR contribute to disease progression. Consequently, significant effort has been undertaken to identify and characterize numerous coactivators and corepressors of AR. Here we report that the transcription factor c-Jun, a basic region leucine zipper (bZIP) transcription factor and is an important member of the AP-1 family, acts as a transcriptional repressor to inhibit the AR transcriptional activity. Furthermore, we have found that c-Jun also represses the transcription of AR. Overexpression of c-Jun in LNCaP prostate cancer cells inhibited luciferase reporters driven by the androgen-induced prostate-specific antigen (PSA) promoter, probasin promoter, mouse mammary tumor virus (MMTV) promoter and tandem repeats of androgen response elements in a dose-dependent manner. Conversely, knockdown of c-Jun enhanced androgen-stimulated AR activity in LNCaP cells. To further confirm the results, we generated a doxycycline-inducible c-Jun overexpression LNCaP stable cell line using lentivrial system. Consistent with the results of promoter activity assay, induction of c-Jun by doxycycline inhibited both steady state and androgen-induced PSA mRNA and protein levels. Interestingly, the protein and mRNA of AR were also downregulated when c-Jun was induced, suggesting that c-Jun suppresses AR expression at the transcriptional level. Moreover, c-Jun induction resulted in a significant reduction in cell number, suggesting that c-Jun suppresses LNCaP cell proliferation by antagonizing AR signaling. In summary, our results suggest that c-Jun negatively regulates the AR signaling by a dual mechanism. Future identification of negative regulators of c-Jun expression will provide a new opportunity to develop novel therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 941. doi:1538-7445.AM2012-941