DAB2IP/AIP1异构体转换的表观遗传调控及在前列腺癌转移中的作用

DAB2IP/AIP1是Ras-GTP酶活化蛋白家族新成员，是受表观遗传调控的抑癌基因，其在前列腺癌发生及转移过程中具有重要作用。我们前期研究发现在高转移的肿瘤细胞中存在一种DAB2IP高表达的新异构体，且促进肿瘤细胞迁移，提示DAB2IP存在异构体转换（Isoform Switching），但其转换的调控机制及在前列腺癌转移中的作用尚未明确。本课题拟在前期研究基础上，通过启动子活性分析和染色质免疫沉淀、甲基化分析等技术分析DAB2IP异构体转换的表观遗传调控机制；通过基因功能获得和功能缺失策略，体内体外研究DAB2IP异构体转换在前列腺癌转移中的作用，并分析其作用机制；通过已制备异构体特异性抗体，进一步在前列腺癌组织中验证。本研究将从分子-细胞-整体水平揭示DAB2IP异构体转换调控及在前列腺癌转移中的作用。本研究为发现新的前列腺癌转移分子标记和开展异构体特异性靶向干预提供理论依据。

DAB2IP/AIP1, which is a novel member of Ras GTPase-activating protein family, is a tumor suppressor gene regulated by epigenetic modification.It plays an important role in prostate cancer development and metastasis.In our previous study, a novel DAB2IP/AIP1 isoform highly expressed in metastatic tumor cells was identified, and increased tumor cell migration, suggesting DAB2IP/AIP1 displays isoform switching.However,the function and regulation mechanism of DAB2IP/AIP1 isoform switching in prostate cancer metastasis is largely unknown. Based on our previous finding,in this project, we will investigate epigenetic regulation mechanism of DAB2IP/AIP1 isoform switching via report gene assay,ChIP assay and DNA methylation analysis. Moreover, we will determine the function of DAB2IP/AIP1 isoform switching in prostate cancer metastasis in vivo and intro by gene gain-of-function and loss-of function strategy,and explore molecular mechanism. Furthermore, we will confirm expression and epigenetic modification of isoform switching in prostate cancer tissues via isoform-specific antibodies. This project will ont only provide a novel insight into elucidating the function and regulation of DAB2IP/AIP1 isoform switching in prostate cancer metastasis, but provide important theoretical foundation for identifying molecular marker in metastasis and developing isoform specific-target intervention.