Abstract LB-74: The NLR-related protein NWD1 is associated with prostate cancer and modulates androgen receptor signaling

Abstract

Abstract Prostate cancer (PCa) is among the leading causes of cancer-related death in men. Androgen receptor (AR) signaling plays a seminal role in prostate development and homeostasis, and dysregulation of this pathway is intimately linked to prostate cancer pathogenesis and progression. Here, we identify the cytosolic NLR-related protein NWD1 as a novel modulator of AR signaling. We determined that expression of NWD1 becomes elevated during prostate cancer progression, based on analysis of primary tumor specimens. Experiments with cultured cells showed that NWD1 expression is up-regulated by the sex-determining region Y (SRY) proteins. Gene silencing by short hairpin RNA (shRNA), in conjunction with transcriptional profiling, showed that NWD1 is required for expression of PDEF (prostate-derived Ets factor), which is known to bind and co-regulate AR. Of note, NWD1 modulates AR protein levels. Silencing NWD1 in PCa cell lines reduces the levels of androgen-stimulated accumulation of nuclear AR and suppresses activity of androgen-driven reporter genes. NWD1 knockdown potently suppressed growth of androgen-dependent LNCaP prostate cancer cells, thus showing its functional importance in an AR-dependent tumor cell model. Proteomics analysis suggested that NWD1 associates with various molecular chaperones commonly related to AR complexes. Altogether, our data suggest a role for tumor-associated over-expression of NWD1 in the dysregulation of AR signaling in PCa. Citation Format: Ricardo G. Correa, Maryla Krajewska, Carl F. Ware, Motti Gerlic, John C. Reed. The NLR-related protein NWD1 is associated with prostate cancer and modulates androgen receptor signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-74. doi:10.1158/1538-7445.AM2014-LB-74