Functional Analysis of the Chromatin Remodeling Factor SRCAP in Prostate Cells

描述（由申请人提供）：前列腺癌的发病率在美国相当高，并且仍然是男性癌症死亡的第二大常见原因。因此，前列腺癌需要新的治疗策略。为了开发新的治疗方式，重要的是要破译参与前列腺癌发展和进展的特定分子机制。有证据表明在癌症发展中染色质重塑复合物蛋白的异常表达。染色质结构的调节通常调节蛋白质访问DNA的能力，因此，在调节转录，复制和基因组稳定性等关键过程中非常重要。染色质重塑酶的突变加速细胞周期进程，在致癌转化和肿瘤生长停滞途径中发挥作用。SNF 2相关CBP激活蛋白（SRCAP）是一种ATP酶，是一种大型多蛋白染色质重塑复合物的核心亚基，并将组蛋白变体H2A.Z掺入核小体。组蛋白H2A.Z是生存力所必需的，参与转录调控并在细胞周期进程中发挥作用。我们的初步研究表明，SRCAP在前列腺癌细胞中起促增殖作用。通过siRNA实验降低前列腺癌细胞中SRCAP表达导致细胞增殖降低。我们还观察到SRCAP调节六个关键细胞周期控制基因的表达。该提案中提出的主要假设是SRCAP促进前列腺癌细胞生长。本研究的具体目的是：（1）探讨SRCAP介导前列腺癌细胞增殖信号的机制。我们将进行细胞周期分析，并使用ChIP-seq分析确定前列腺癌细胞中的全基因组SRCAP和H2A.Z结合。(2)评估SRCAP耗竭对前列腺癌异种移植肿瘤模型中肿瘤生长的影响。我们提出了新的方向，涉及SRCAP和H2A.Z在前列腺癌之间的相互作用。这项研究有望揭示与前列腺癌发病和进展相关的新机制。该提案中概述的研究希望能够深入了解SRCAP在前列腺癌细胞生物学中的功能作用。从这些研究中获得的信息可用于靶向抑制癌细胞增殖的新途径 公共卫生相关性：调节细胞生长的分子途径在癌症的发展和进展中很重要。本申请中提出的研究试图理解染色质重塑因子SRCAP在控制前列腺癌细胞生长中的作用。这项研究的结果有可能揭示细胞生长调控的新机制，并确定癌症治疗的新靶点。

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.