Role of Jmjd1a in hypoxia-induced EMT and prostate cancer stem cells

描述（由申请人提供）：前列腺癌是美国男性中最常见的恶性肿瘤。侵袭性前列腺肿瘤的标志是存在神经内分泌分化（NED）病变、表达NE和干细胞标志物的细胞簇。我们发现HIF与NE特异性转录因子FoxA 2共同诱导一个转录程序，该程序决定了人前列腺癌的NED表型。在由HIF和FoxA 2共同调控的基因中，有一种名为Jmjd 1a的基因，它是一种激活基因表达的组蛋白H3 K9去甲基化酶。在目标1中，我们将测试Jmjd 1a被HIF和AR招募到Slug和ZEB 2启动子的假设，在那里它触发H3 K9去甲基化并促进HIF介导的Slug和ZEB 2转录，从而诱导EMT程序。ChIP芯片和微阵列分析，提出了研究的全球作用Jmjd 1a EMT基因表达。在目标2中，我们将使用原位前列腺肿瘤模型研究Jmjd 1a依赖性Slug、ZEB 2和Aim 1中鉴定的基因表达在缺氧诱导的EMT和转移中的生物学作用。目的3：研究HIF、Jmjd 1a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。通过检验组蛋白去甲基化酶Jmjd 1a在EMT和前列腺干细胞中起核心作用的假设，我们提出的研究将建立HIF和Jmjd 1a在这些前列腺癌表型中的缺氧依赖性作用的新范式，这些前列腺癌表型与恶性肿瘤，预后不良和对治疗的抗性相关，从而为前列腺癌提供新的治疗方式。 K99奖将提供一种方法，将研究从最初的指导阶段，重点是鉴定和初步表征Jmjd 1a调节的蛋白质，这些蛋白质有助于低氧下的EMT和前列腺癌干细胞，到独立阶段，工作将集中在Jmjd 1a和HIF在低氧驱动的前列腺干细胞中的作用。SBMRI将提供一个良好的环境（详见设施和其他资源以及机构环境部分）来指导和指导我的研究，并发展我的独立研究。K99奖和SMBRI将作为我学术生涯开始的杰出基础。在利用尖端技术，系统，程序和设施的同时，我将有独特的机会得到癌症生物学，信号转导，前列腺癌干细胞，基因表达调控和表观遗传学领域的领导者的指导（如我的职业发展计划中所述）。凭借生物化学，分子和细胞生物学的背景，我觉得这个奖项，通过其指导和独立阶段，将使我能够向前迈进，并为新的和新兴的研究做出巨大贡献，这些研究专注于我提出的涉及缺氧，EMT，前列腺干细胞和表观遗传学的研究。 公共卫生相关性：拟议的研究将表征表观遗传控制的作用，通过组蛋白去甲基化酶-Jmj 1a-在缺氧诱导的EMT中，以及这种新的调节轴对前列腺癌干细胞和正常前列腺干细胞的影响。由于EMT和干细胞样表型与肿瘤进展、转移、预后不良和治疗耐药性密切相关，我们提出的研究提供了推动人类前列腺癌进展的新机制，并对靶向治疗和监测产生影响。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The proposed studies will characterize the role of epigenetic control, by histone demethylase - Jmj1a - in hypoxia-induced EMT, and the implication of this new regulatory axis to prostate cancer stem cells and normal prostate stem cells. Because EMT and stem cell-like phenotypes are tightly associated with tumor progression, metastasis, poor prognosis and therapeutic resistance, our proposed studies offer novel mechanisms driving the progression of human prostate cancer, with implications for targeted therapy and monitoring.