Non-coding RNAs for Epigenetic Transcriptional Silencing in Prostate Cancer

用于前列腺癌表观遗传转录沉默的非编码 RNA

• 批准号: 8602051
• 负责人: Martin John Walsh
• 金额: $ 4.18万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8602051
• 关键词: Affinity; Age; Antisense RNA; Binding; Binding Sites; Biology; CDKN2A gene; Cancer Biology; Cell Line; Cellular biology; Chemicals; Chromatin; Combinatorial Synthesis; Complex; Development; Disease; EZH2 gene; Epigenetic Process; Epithelial Cells; Fluorescence Polarization; Functional RNA; Future; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Goals; Health; Histone H3; Homeobox Genes; Human; Human Biology; Human Genome; Investigation; Ligands; Link; Longevity; Lysine; Malignant Epithelial Cell; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Methods; Methylation; Methyltransferase; Molecular; Oncogenes; Outcome; PRC1 Protein; Peptides; Physical condensation; Play; Polycomb; Precipitation; Prevention; Process; Prostate; Prostate carcinoma; Prostatic; Prostatic Intraepithelial Neoplasias; Protein Family; Proteins; Public Health; RNA; RNA Binding; Recruitment Activity; Repression; Research; Role; Site; Staging; Stimulus; Stress; Structure; Structure-Activity Relationship; Testing; Therapeutic; Transcript; Transcriptional Regulation; United States; base; design; disease diagnosis; epigenome; human disease; in vivo; men; mutant; novel; outcome forecast; prostate cancer prevention; public health relevance; scaffold; screening; senescence; small molecule; success; tool

DESCRIPTION (provided by applicant): Prostate cancer afflicts 1 in 4 men by the age of 75 and remains a major public health concern in the United States. Despite some success in disease diagnosis and treatment the molecular parameters that influence the transition from prostatic intraepithelial neoplasia to prostate cancer has remained elusive. The long-term goal of our research is to determine the fundamental molecular mechanisms of epigenetic gene transcription in human biology and disease, particularly human prostate cancer. We focus on the role of Polycomb repressive complexes (PRCs) in transcriptional control of the INK4a/ARF locus, gene products of which are the primary mediators of oncogene-induced senescence. PRC-directed gene silencing is mediated by methylation of histone H3 lysine 27 (H3K27me) at target loci in chromatin that is initiated by the lysine methyltransferase EZH2 of the PRC2 and followed by H3K27me association with the PRC1 by binding to chromobox (CBX) proteins, resulting in chromatin condensation and target gene silencing. Our recent study reveals that the silencing activity of PRC1 for the INK4a/ARF locus requires CBX7 interactions with a non-coding RNA transcript ANRIL (the antisense RNA of INK4a locus) and H3K27me via its conserved chromodomain, highlighting a direct role of long non-coding RNA in epigenetic transcriptional silencing. CBX7 and other key components of PRCs that play a key role in cellular lifespan extension by repressing the INK4a/ARF locus are over-expressed in prostate cancer. We further observed in our study markedly elevated expression of ANRIL, CBX7 and EZH2 and a corresponding decrease in p16Ink4a expression in prostate cancer as compared to normal prostate epithelial cells. However, the molecular mechanism of non-coding RNA in PRC-directed gene silencing is not clear. In this project, we aim to determine the molecular underpinning of the functional interplay between non-coding RNA and H3K27me in gene silencing by the PRCs in normal prostate epithelial cells, as well as during the conversion of prostatic intraepithelial neoplasia into prostate carcinoma using combined chromatin/cell biology and structural/chemical biology methods. We expect that the results emerging from our studies including novel chemical tools will have profound impact on a better understanding of prostate cancer biology and future advance of therapeutic means for prognosis and prevention of human prostate cancer.

描述（由申请人提供）： 75 岁之前，四分之一的男性患有前列腺癌，并且仍然是美国主要的公共卫生问题。尽管在疾病诊断和治疗方面取得了一些成功，但影响前列腺上皮内瘤变向前列腺癌转变的分子参数仍然难以捉摸。我们研究的长期目标是确定人类生物学和疾病（特别是人类前列腺癌）中表观遗传基因转录的基本分子机制。我们重点研究 Polycomb 抑制复合物 (PRC) 在 INK4a/ARF 位点转录控制中的作用，其基因产物是癌基因诱导衰老的主要介质。 PRC 介导的基因沉默是通过染色质目标位点上组蛋白 H3 赖氨酸 27 (H3K27me) 的甲基化介导的，该甲基化由 PRC2 的赖氨酸甲基转移酶 EZH2 启动，随后 H3K27me 通过与染色体盒 (CBX) 蛋白结合而与 PRC1 关联，从而导致染色质浓缩和目标基因沉默。我们最近的研究表明，PRC1 对 INK4a/ARF 位点的沉默活性需要 CBX7 通过其保守的染色结构域与非编码 RNA 转录本 ANRIL（INK4a 位点的反义 RNA）和 H3K27me 相互作用，强调了长非编码 RNA 在表观遗传转录沉默中的直接作用。 CBX7 和 PRC 的其他关键成分通过抑制 INK4a/ARF 位点在细胞寿命延长中发挥关键作用，在前列腺癌中过度表达。我们在研究中进一步观察到，与正常前列腺上皮细胞相比，前列腺癌中 ANRIL、CBX7 和 EZH2 的表达显着升高，p16Ink4a 表达相应降低。然而，非编码RNA在PRC介导的基因沉默中的分子机制尚不清楚。在这个项目中，我们的目标是使用染色质/细胞生物学和结构/化学生物学相结合的方法，确定正常前列腺上皮细胞中PRC基因沉默中以及前列腺上皮内瘤变转化为前列腺癌过程中非编码RNA和H3K27me之间功能相互作用的分子基础。我们预计，我们的研究结果（包括新型化学工具）将对更好地了解前列腺癌生物学以及人类前列腺癌预后和预防治疗手段的未来发展产生深远影响。