Role of JMJD1A in hypoxia-induced EMT and prostate cancer stem cells

摘要 前列腺癌是美国男性最常见的恶性肿瘤。侵袭性前列腺癌的特征 肿瘤是指存在神经内分泌分化(NED)损害，表达NE和 干细胞标记物。我们已经发现，HIF与NE特异的转录因子FoxA2合作， 诱导决定人类前列腺癌NED表型的转录程序。在这些人中 受HIF和FOXA2共同调控的基因是Jmjd1a，这是一种激活基因的组蛋白H3K9去甲基酶 表情。在目标1中，我们将检验Jmjd1a被HIF和AR招募为鼻涕虫启动子的假设 和ZEB2，在那里它触发H3K9去甲基化并促进HIF介导的slug和ZEB2的转录 这反过来又引发了EMT计划。提出了芯片上芯片和微阵列分析来研究全球 Jmjd1a在EMT基因表达中的作用在目标2中，我们将研究它的生物学作用。 Jmjd1a依赖的Slug、ZEB2和Aim1基因在低氧诱导的EMT中的表达 使用原位前列腺癌模型进行转移。在目标3中，我们将研究HIF、Jmjd1a及其 靶基因KLF-4在前列腺癌干细胞和正常前列腺干细胞自我更新和分化中的作用 细胞。通过验证组蛋白去甲基酶Jmjd1a在EMT和 前列腺干细胞，我们提出的研究将为HIF的缺氧依赖作用建立一个新的范例 和Jmjd1a在这些前列腺癌表型中与恶性肿瘤、不良预后和 抵抗治疗，从而为前列腺癌提供了新的治疗方式。 K99奖将提供从最初的指导阶段开始进行研究的手段，即 重点是鉴定和初步鉴定Jmjd1a调节的参与EMT和 前列腺癌干细胞在低氧条件下向独立期的作用将成为工作的重点。 低氧驱动的前列腺干细胞中的Jmjd1a和HIF。SBMRI将提供良好的环境(请参见 设施及其他资源和机构环境部分以了解详细信息)来指导和指导我的 研究和发展我的独立研究。K99大奖和SMBRI将成为杰出的 为我学术生涯的开始奠定了基础。在利用尖端技术的同时 可用的技术、系统、程序和设施，我将有独特的机会接受指导 由癌症生物学、信号转导、前列腺癌干细胞、基因表达等领域的领导者 监管和表观遗传学(详见我的职业发展计划)。他有生物化学背景， 分子和细胞生物学，我觉得这个奖项，通过其指导和独立阶段，将是独一无二的 让我继续前进，为新的和新兴的研究做出巨大贡献 拟议的研究涉及缺氧、EMT、前列腺干细胞和表观遗传学。

ABSTRACT Prostate cancer is the most common malignancy in American men. A hallmark of aggressive prostate tumor is the presence of neuroendocrine differentiation (NED) lesions, clusters of cells expressing NE and stem cell markers. We have found that HIF, in cooperation with a NE-specific transcription factor FoxA2, induces a transcriptional program that determines the NED phenotype of human prostate cancer. Among the genes co-regulated by HIF and FoxA2 is Jmjd1a, a histone H3K9 demethylase that activates gene expression. In Aim 1, we will test the hypothesis that Jmjd1a is recruited by HIF and AR to promoters of Slug and ZEB2, where it triggers H3K9 demethylation and facilitates HIF-mediated transcription of Slug and ZEB2 that in turn induces the EMT program. ChIP-on-chip and microarray analyses are proposed to study global role of Jmjd1a for EMT gene expression. In Aim 2, we will investigate the biological role of Jmjd1a-dependent expression of Slug, ZEB2 and genes identified in Aim1 in hypoxia-induced EMT and metastasis using an orthotopic prostate tumor model. In Aim 3, we will study role of HIF, Jmjd1a and their target gene KLF-4 in self-renewal and differentiation of prostate cancer stem cells and normal prostate stem cells. By testing the hypothesis that the histone demethylase Jmjd1a plays a central role in EMT and prostate stem cells, our proposed studies will establish a new paradigm for hypoxia-dependent role of HIF and Jmjd1a in these prostate cancer phenotypes that are associated with malignancy, poor prognosis and resistance to therapy, thereby providing novel therapeutic modalities for prostate cancer. The K99 Award will provide the means to take the research from the initial mentored phase, which is focused on identification and initial characterization of Jmjd1a regulated proteins that contribute to EMT and prostate cancer stem cells under hypoxia to the independent phase where the work will focus on the role of Jmjd1a and HIF in hypoxia driven prostate stem cells. SBMRI will provide an excellent environment (see Facilities and Other Resources and Institutional Environment sections for details) to mentor and guide my research and to develop my independent studies. The K99 Award and SMBRI will serve as an outstanding foundation for the beginning of my academic career. While taking advantage of the cutting edge technologies, systems, programs, and facilities available I will have the distinct opportunity to be mentored by leaders in the fields of cancer biology, signal transduction, prostate cancer stem cells, gene expression regulation and epigenetics (as detailed in my Career Development Plan). With a background in biochemistry, molecular and cell biology, I feel this Award, via both its Mentored and Independent Phases, will uniquely position me to move forward and contribute immensely to new and emerging studies that focus on my proposed research involving hypoxia, EMT, prostate stem cells and epigenetics.