Functional Analysis of the Chromatin Remodeling Factor SRCAP in Prostate Cells

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DESCRIPTION (provided by applicant): The incidence of prostate cancer is quite high in the United States and continues to be the second most common cause of cancer death in men. Therefore, novel therapeutic strategies are needed for prostate cancer. In order to develop new treatment modalities, it is important to decipher the specific molecular mechanisms involved in prostate cancer development and progression. There is evidence implicating aberrant expression of chromatin remodeling complex proteins in cancer development. Regulation of chromatin structure often modulates the ability of proteins to access DNA, and therefore, is important in regulating key processes like transcription, replication and genome stability. Mutations in chromatin remodeling enzymes accelerate cell cycle progression, play a role in oncogenic transformation, and inactivate growth arrest pathways. The SNF2-related CBP activator protein (SRCAP) is an ATPase that is the core subunit of a large multiprotein chromatin remodeling complex and incorporates the histone variant H2A.Z into nucleosomes. Histone H2A.Z is essential for viability, is involved in transcriptional regulation and plays a role in cell cycle progression. Our preliminary studies indicate that SRCAP plays a pro-proliferative role in prostate cancer cells. Reduction of SRCAP expression in prostate carcinoma cells by siRNA experiments results in decreased cellular proliferation. We also observed that SRCAP regulates expression of six key cell cycle control genes. The major hypothesis addressed in this proposal is that SRCAP promotes prostate cancer cell growth. The specific aims are: (1) To determine the mechanisms by which SRCAP mediates proliferative signaling in prostate carcinoma cells. We will perform cell cycle analysis and determine genome-wide SRCAP and H2A.Z binding in prostate cancer cells using ChIP- seq analysis. (2) To assess the effects of SRCAP depletion on tumor growth in a prostate cancer xenograft tumor model. We propose novel directions that involve the interactions between SRCAP and H2A.Z in prostate cancer. This study has the promise of uncovering novel mechanism associated with prostate cancer incidence and progression. The studies outlined in this proposal hope to provide insight into the functional role of SRCAP in the biology of prostate cancer cells. Information obtained from these studies can be used to target novel pathways to inhibit cancer cell proliferation PUBLIC HEALTH RELEVANCE: Molecular pathways that regulate cell growth are important in the development and progression of cancer. Studies proposed in this application seek to understand the role of the chromatin remodeling factor SRCAP in controlling prostate cancer cell growth. Results from the proposed work have the potential to unveil novel mechanisms of cell growth regulation and to identify novel targets for cancer therapy.