新因子hARAP3在AR介导基因转录调控及前列腺癌中的作用及机制

项目名称： 新因子hARAP3在AR介导基因转录调控及前列腺癌中的作用及机制

项目编号： No.31271364

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 赵越

作者单位： 中国医科大学

项目金额： 80万元

中文摘要： AR是核受体超家族成员，以配体依赖方式介导基因转录，并招募一系列辅调节因子调控其转录，发挥其生物学功能。AR及其辅调节因子分别在雄激素依赖和去势抵抗前列腺癌（CRPC）中扮演着重要角色。本项目利用AR-PEV果蝇模型筛选出AR新辅调节因子hARAP3。该因子属CK1蛋白激酶家族，含有对多种蛋白有磷酸化作用的丝/苏氨酸蛋白激酶结构域。前期工作中，我们验证了hARAP3对AR介导基因转录显著上调；还发现干扰hARAP3蛋白表达减少了组蛋白H3S10ph及H3K9Ac水平；此外，hARAP3在PC肿瘤组织中随分化程度降低呈高表达趋势，并在2种CRPC细胞中高表达，提示hARAP3可能在PC，特别是CRPC转化过程中起关键作用。我们将深入解析hARAP3参与转录调控的表观遗传学机制，研究其在PC生长、侵袭转移及去势抵抗等方面的作用，试图分析其分子机制，为该疾病的预防和治疗提供理论依据和新的靶点。

中文关键词： 雄激素受体；辅调节因子；转录调控；表观遗传学机制；前列腺癌

英文摘要： AR is a member of nuclear receptor superfamily and induces target gene transcription in a ligand-dependent manner. In this process, AR recruits a series of co-regulators to modulate AR-mediated transactivation and exerts its biological functions. AR and its co-regulators individually play important roles in Androgen dependent (ADPCa) and Androgen independent/castration resistant prostate cancers (AIPCa/CRPC). By AR-position effect variegation (AR-PEV) Drosophila experimental model, we selected a series of new co-regulators involved in AR-mediated transactivation and named as of AR associated proteins (ARAPs). These co-regulators include DNA damage checkpoint factors (ARAP1 and ARAP2), Ser/Thr protein kinase (ARAP3), RNA binding protein (ARAP4) and a factor with unknown function. Based on the preliminary experiments, we selected one of them (ARAP3) for further study in this grant. Both ARAP3 and its human homologue (hARAP3) belong to casein kinase 1 (CK1) protein family and contain S/T Kc domain, which phosphorylates many kinds of proteins. In the previous studies, we examined hARAP3 significantly enhanced AR-mediated transactivation. We also found that sihARAP3 decreased the level of histone H3S10 phosphorylation (H3S10ph) and H3K9 acetylation (H3K9Ac). Furthermore, hARAP3 is overexpressed in human prostate can

英文关键词： androgen receptor；coregulator；transcriptional regulation；epigenetic mechanism；prostate cancer