Role of the Histone demethylase JARID1d in Epigenetic Events of Prostate Cancer

组蛋白去甲基化酶 JARID1d 在前列腺癌表观遗传事件中的作用

• 批准号: 8296574
• 负责人: Min Gyu Lee
• 金额: $ 29.63万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-05 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296574
• 关键词: Affect; Architecture; Biochemical; Bioinformatics; Biological; Biological Process; Cancerous; Cells; Chromatin; Development; Epigenetic Process; Event; Family; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Mutation; Gene Targeting; Genes; Goals; Histone H3; Histones; Human; In Vitro; Location; Lysine; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Mediating; Methylation; Molecular; Mutation; Neoplasm Metastasis; Normal tissue morphology; Nucleic Acid Regulatory Sequences; Oncogene Activation; Oncogenes; Phenotype; Play; Promoter Regions; Prostate; Prostatic Neoplasms; Proteins; Regulation; Role; Screening procedure; Signal Transduction; Techniques; Therapeutic Agents; Tumor Cell Invasion; Tumor Suppressor Genes; Tumor-Suppressor Gene Inactivation; United States; base; cancer cell; cell type; chromatin immunoprecipitation; demethylation; driving force; genetic regulatory protein; genome-wide; histone modification; in vitro Assay; in vivo; innovation; insight; male; member; men; methyl group; mouse model; novel; novel therapeutics; reconstitution; research study; small molecule; tumor progression

DESCRIPTION (provided by applicant): In addition to genetic alterations, epigenetic changes- heritable changes in gene expression or cellular phenotypes without DNA alterations - are a major driving force for prostate cancer events. In contrast to great advance in our understanding of genetic alterations, the molecular basis underlying epigenetic changes remains to be further explored. Histone lysine (K) methylation has emerged as a hallmark associated with epigenetic regulation of gene expression. In particular, trimethylation at histone H3 lysine 4 (trimethyl H3K4) is a genome-wide epigenetic signal that occupies and affects 75% of all the gene-regulatory regions. Alterations in the global and local profile of this key epigenetic signal commonly occur in many advanced prostate tumors and are associated with oncogene activation and tumor suppressor gene inactivation. However, it is unknown how such alterations in trimethyl H3K4 profiles occur in prostate cancer cells. The long-term objective of the proposed study is to characterize the molecular mechanisms responsible for epigenetic events associated with alterations in trimethyl H3K4 profiles in advanced prostate cancer. In a recent breakthrough study, we identified JARID1d as a novel "male-specific" histone demethylase that is capable of "removing methyl groups" (demethylating) from trimethyl and dimethyl H3K4 (Cell, 2007). In addition, our bioinformatic analysis showed that JARID1d levels are dysregulated in advanced prostate tumors, indicating an importance role for JARID1d in epigenetic changes involving alterations in trimethyl H3K4 during prostate cancer events. Our preliminary studies identified novel JARID1d-associated proteins that are likely involved in the recruitment and the molecular regulation of JARID1d. Based on these exciting, definitive findings, our central hypothesis is that dysregulation of JARID1d plays a key role in epigenetic alterations in trimethyl H3K4 profiles at JARID1d target genes and consequently contributes to prostate cancer events. In the proposed study, we focus on understanding the role and regulation of JARID1d in epigenetic changes associated with trimethyl H3K4 alterations during prostate cancer events. Specific Aims are to 1) Determine the chromatin locations and recruitment mechanisms of JARID1d; 2) Elucidate the molecular mechanisms that regulate JARID1d-mediated demethylation; 3) Determine the role of JARID1d in prostate tumor progression and metastasis. Our proposed studies are fundamental to understanding the molecular mechanisms underlying a common epigenetic event, i.e., alterations in trimethyl H3K4 profiles, in advanced prostate tumors and will uncover an unprecedented role for the epigenetic modifier JARID1d in prostate tumor progression and invasion.

描述（由申请人提供）：除了遗传改变之外，表观遗传变化（基因表达或细胞表型的可遗传变化，没有 DNA 改变）是前列腺癌事件的主要驱动力。与我们对遗传改变的理解的巨大进步相反，表观遗传变化背后的分子基础仍有待进一步探索。组蛋白赖氨酸 (K) 甲基化已成为与基因表达的表观遗传调控相关的标志。特别是，组蛋白 H3 赖氨酸 4（三甲基 H3K4）的三甲基化是一种全基因组表观遗传信号，占据并影响所有基因调控区域的 75%。这种关键表观遗传信号的整体和局部特征的改变通常发生在许多晚期前列腺肿瘤中，并且与癌基因激活和抑癌基因失活相关。然而，目前尚不清楚三甲基 H3K4 谱的这种改变如何在前列腺癌细胞中发生。拟议研究的长期目标是确定与晚期前列腺癌三甲基 H3K4 谱变化相关的表观遗传事件的分子机制。在最近的一项突破性研究中，我们确定 JARID1d 是一种新型“男性特异性”组蛋白去甲基化酶，能够从三甲基和二甲基 H3K4 中“去除甲基”（去甲基化）（Cell，2007）。此外，我们的生物信息学分析表明，JARID1d 水平在晚期前列腺肿瘤中失调，表明 JARID1d 在前列腺癌事件期间涉及三甲基 H3K4 改变的表观遗传变化中发挥重要作用。我们的初步研究发现了新的 JARID1d 相关蛋白，这些蛋白可能参与 JARID1d 的招募和分子调控。基于这些令人兴奋的明确发现，我们的中心假设是，JARID1d 的失调在 JARID1d 靶基因三甲基 H3K4 谱的表观遗传改变中发挥关键作用，从而导致前列腺癌事件。在拟议的研究中，我们重点了解 JARID1d 在前列腺癌事件期间与三甲基 H3K4 改变相关的表观遗传变化中的作用和调节。具体目标是 1) 确定 JARID1d 的染色质位置和招募机制； 2）阐明调节JARID1d介导的去甲基化的分子机制； 3)确定JARID1d在前列腺肿瘤进展和转移中的作用。我们提出的研究对于理解晚期前列腺肿瘤中常见表观遗传事件（即三甲基 H3K4 谱的改变）的分子机制至关重要，并将揭示表观遗传修饰剂 JARID1d 在前列腺肿瘤进展和侵袭中前所未有的作用。