Abstract 759: Regulation of androgenic signaling by yes-associated protein, YAP, in prostate cancer cells.

Abstract

Abstract Androgenic signaling plays a central role in prostate tumor development, progression, and metastasis. The molecular circuitry contributing to these pathological events is still a mystery. Previously, we reported that the hippo-like protein kinase Mst1/2 antagonized androgen receptor (AR) and prostate tumor cell growth (Cinar et al., Cancer Res., 2011). Here, we studied the role of yes-associated protein (YAP) oncogene, a prominent nuclear effector of the Mst/Hippo tumor suppressor network, in regulating AR and in prostate tumor cell growth in vitro. As revealed by co-immunoprecipitation (IP) and western blot experiments, we first showed that endogenous YAP formed protein complexes with endogenous AR. The complex formation between the two proteins mainly occurred in cell nuclei was further enhanced by androgen stimulation. Our luciferase-promoter reporter analysis demonstrated that enforced YAP expression increased the androgen-mediated and AR-responsive promoter reporter gene activation, and the carboxyl-terminal site of YAP, which consists of PDZ and coiled-coiled protein-protein interaction domains, appeared to be responsible for AR transactivation. Chromatin-IP and PCR analysis of the bound and uncross-linked genomic DNA revealed that YAP interacted with the DNA regions where AR also binds, and androgen enhanced the interaction between YAP and chromatin DNA. We also provided evidence that, compared to vector control, enforced YAP expression promoted androgen-dependent and independent cell growth, and silencing YAP by RNAi reduced the growth of castration-resistant prostate tumor cells in vitro. Our findings indicate that YAP is a physiologic binding partner and positive regulator of androgenic signaling, and suggest that the Hippo-YAP pathway plays a critical role in human prostate tumor progression. Citation Format: Ahmet Alptekin, Gamze Kuser Abali, Qiang Wang, Bekir Cinar. Regulation of androgenic signaling by yes-associated protein, YAP, in prostate cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 759. doi:10.1158/1538-7445.AM2013-759