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

JMJD1A 在缺氧诱导 EMT 和前列腺癌干细胞中的作用

• 批准号: 8733791
• 负责人: Jianfei Qi
• 金额: $ 23.41万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8733791
• 关键词: American; Androgen Receptor; Androgens; Automobile Driving; Award; Biochemistry; Biological; C-KIT Gene; CD44 gene; Cancer Biology; Cell physiology; Cells; Cellular biology; ChIP-on-chip; Data; Dependency; Development; Development Plans; Dyes; Environment; Enzymes; Epigenetic Process; Epithelial Cells; Event; Exhibits; Foundations; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Histones; Human; Hypoxia; In Vitro; Invaded; Lentivirus Vector; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mentors; Mesenchymal; Modality; Modeling; Molecular Biology; Monitor; Mus; Neoplasm Metastasis; Neurosecretory Systems; PKH 26; Phase; Phenotype; Play; Positioning Attribute; Property; Prostate; Prostate Adenocarcinoma; Prostate Neuroendocrine Neoplasm; Prostatic Neoplasms; Proteins; Recruitment Activity; Regulation; Research; Resistance; Resources; Role; Signal Transduction; Stem Cell Factor; Stem cells; System; Technology; Testing; Therapeutic; Transcript; Work; cancer cell; cancer stem cell; career; career development; demethylation; design; embryonic stem cell; epithelial to mesenchymal transition; hormone therapy; hypoxia inducible factor 1; in vivo Model; matrigel; men; novel; novel therapeutics; outcome forecast; programs; promoter; prostate cancer cell; protein expression; research study; self-renewal; slug; small hairpin RNA; therapy resistant; transcription factor; tumor; tumor progression; tumor xenograft; tumorigenesis

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.

摘要 前列腺癌是美国男性最常见的恶性肿瘤。前列腺增生的一个标志 肿瘤是神经内分泌分化（NED）病变的存在，表达NE的细胞簇和 干细胞标志物我们已经发现，HIF与NE特异性转录因子FoxA 2合作， 诱导决定人前列腺癌NED表型的转录程序。中 由HIF和FoxA 2共同调节的基因是Jmjd 1a，它是一种组蛋白H3 K9去甲基化酶， 表情在目的1中，我们将检验Jmjd 1a被HIF和AR募集到Slug启动子的假设。 和ZEB 2，其中它触发H3 K9去甲基化并促进HIF介导的Slug和ZEB 2转录 这反过来又导致了EMT计划。ChIP芯片和微阵列分析被提出来研究全球 Jmjd 1a对EMT基因表达的作用。在目标2中，我们将研究 缺氧诱导EMT中Slug、ZEB 2和Aim 1中鉴定的基因的Jmjd 1a依赖性表达， 使用原位前列腺肿瘤模型观察转移。在目的3中，我们将研究HIF，Jmjd 1a及其在细胞凋亡中的作用。 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作用 细胞通过检验组蛋白去甲基化酶Jmjd 1a在EMT中起核心作用的假设， 前列腺干细胞，我们提出的研究将建立一个新的范式缺氧依赖的作用， 和Jmjd 1a在这些前列腺癌表型中与恶性肿瘤、预后差和 从而提供了前列腺癌的新的治疗方式。 K99奖将提供从最初的指导阶段进行研究的手段， 专注于鉴定和初步表征Jmjd 1a调节蛋白，有助于EMT， 前列腺癌干细胞在缺氧状态下到独立阶段的工作将集中在其中的作用 Jmjd 1a和HIF在缺氧驱动的前列腺干细胞中的作用SBMRI将提供良好的环境（参见 设施和其他资源以及机构环境部分），以指导和指导我的 研究和发展我的独立研究。K99奖和SMBRI将作为一个杰出的 这是我学术生涯开始的基础。同时利用尖端技术 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）。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，将独特的 使我能够向前迈进，并为新的和新兴的研究做出巨大贡献，这些研究侧重于我的 建议的研究涉及缺氧，EMT，前列腺干细胞和表观遗传学。