Acetylation of Androgen Receptor in Prostate Growth

Georgetown University, Washington DC

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Abstract

DESCRIPTION (provided by applicant): This proposal aims to determine the role of acetylation modification of the androgen receptor (AR) in the regulation of AR function and its implication in the development of prostate cancer. Prostate cancer is the most commonly diagnosed cancer in American men. Currently there is no effective clinical therapy for hormone-refractory prostate cancer growth. AR mediates androgen-dependent and hormone-refractory prostate tumor growth. Our studies have identified acetylation modification of the AR as a novel mechanism in regulation of the AR function. We found that the AR is a direct target of the histone acetyltransferase p300 and p/CAF, and the acetylation of the AR is essential to its ligand-dependent activation. In addition, AR acetylation mimic mutation confers growth advantage to the prostate cancer cells lines. In the proposed study, we will: 1. Determine the role of AR acetylation in regulating AR function. We will further our study on the physiologic effects of acetylation modification of the AR on its nuclear transportation, its interactions with coactivators and corepressors, and the effects on its protein degradation. 2. Determine the role of AR acetylation in androgen-dependent and androgen-independent AR signaling pathways. We hypothesize that the AR acetylation modification is a key step in the conversion and development of androgen-independent prostate cancer cell growth. We will investigate the potential role of AR acetylation in androgen-independent AR function induced by promiscuous ligands or by cytokines and growth factors such as IL-6 and HER-2/neu signaling. 3. Directly investigate the role of AR acetylation in prostate cell growth and tumorigenesis in vivo using AR acetylation mimic transgenic mice. We will generate and analyze transgenic mice that overexpress an acetylation mimic form mutation ARK630Q controlled by the probasin promoter. This mouse model will allow us to examine in vivo the role of AR acetylation modification in the prostate's embryonic development, cellular growth, and tumor formation. The success of this study will help us to understand the processes in prostate cancer development, especially the mechanism underlying the formation of hormone-refractory tumors. This could lead to the development of novel therapeutic strategies for prostate cancer by intervention of the acetylation process and in addition, it will provide insight into steroid hormone regulation and aging process.