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: 8903769
• 负责人: Jianfei Qi
• 金额: $ 22.72万
• 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/8903769
• 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; Microarray Analysis; Modality; 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; Transcript; Work; cancer cell; cancer stem cell; career; career development; demethylation; design; embryonic stem cell; epigenetic regulation; epithelial to mesenchymal transition; histone demethylase; hormone therapy; hypoxia inducible factor 1; in vivo Model; matrigel; men; novel; novel therapeutics; outcome forecast; programs; promoter; prostate cancer cell; prostate cancer model; protein expression; research study; self-renewal; slug; small hairpin RNA; targeted treatment; 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