Novel epigenetic paradigm in endometrial cancer recurrence

子宫内膜癌复发的新表观遗传学范例

基本信息

批准号：
8755016
负责人：
Tim H.-M. Huang
金额：
$ 30.84万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8755016
关键词：
Adhesions Atomic Force Microscopy Attenuated Binding Biological Markers Cancer Patient Cancer cell line Candidate Disease Gene Cell Adhesion Molecules Cell Line Cells ChIP-seq Characteristics Chromatin Clinical Complex CpG Islands Cultured Cells DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases Data Disease Disease-Free Survival Distant Metastasis EGF gene Endometrial Endometrial Carcinoma Endometrial Neoplasms Endometrium Epidermal Growth Factor Receptor Epigenetic Process Epithelial Gene Expression Gene Targeting Genetic Transcription Genome Growth Histones Hypermethylation Immunohistochemistry Invaded Knock-out Link Maintenance Malignant Neoplasms Mediating Mesenchymal Methylation Microfluidics Modeling Molecular Mutation Neoplasm Metastasis Network-based Normal Cell Oncogenic Pathway interactions Patients Pattern Phenotype Polycomb Primary Neoplasm Receptor Signaling Recruitment Activity Recurrence Recurrent tumor Relative (related person)Reporter Repression Risk Signal Pathway Specific qualifier value Staging Stem cells Subgroup System TACSTD2 gene Testing The Cancer Genome Atlas Tissue Microarray Transcriptional Activation Transplantation Xenograft Model Xenograft procedure base cancer cell cancer recurrence cohort combinatorial epigenetic marker histone methyltransferase molecular marker nanomechanical novel promoter public health relevance pyrosequencing stem time use tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): DNA hypermethylation of promoter CpG islands is known to be associated with transcriptional silencing in endometrial cancer. We recently identified a unique set of CpG island loci that are hypermethylated in non- recurrent tumors but coordinately hypomethylated (or less methylated) in primary tumors that subsequently recurred. The loci can be highly susceptible to de novo DNA methylation (i.e., a default state) partly attributed to the high expression of DNA methyltransferase 1 (DNMT1) and Polycomb Repressor Complex 2 (PRC2). While these loci, which are implicated in epithelial-mesenchymal transition (EMT), are not usually expressed in normal cells, their chromatin may remain in a bivalent state similar to those observed in stem and progenitor cells. Network-based analysis linking these loci to epidermal growth factor receptor (EGFR) signaling suggests that a low DNA methylation signature and a permissive chromatin state can permit transcriptional activation by this pathway. This was confirmed by our functional studies showing that EGF induced the expression of candidate genes via the epithelial adhesion marker (EpCAM) intracellular domain (EpICD). We hypothesize that the binding of EpICD transcriptional complex at target promoters limits the access of DNMT1/PRC2 to these loci and recruits histone methyltransferases to modify the chromatin into an active state in recurrent tumors. This epigenetic overwriting of the default state is necessary for EMT-mediated progression of endometrial cancer cells. In Aim 1, we will validate the methylation status of these candidate loci in an independent cohort of endometrial cancer. DNA hypomethylation and over-expression of these loci can be used as biomarkers for predicting risk of endometrial cancer recurrence in patients. In Aim 2, we will assess whether EGF-induced EMT leads to identification of EpICD target genes delineating novel candidate hypomethylators. Associated mesenchymal characteristics of EGF-induced cells will be examined by molecular means and cellular nanomechanical features indicative of increased invasiveness. In Aim 3, we will determine whether the EpICD transcription complex is a key factor of this epigenetic reprogramming. EpICD binding to target promoters is expected to diminish the binding of DNMT1/PRC2 and alter combinatorial patterns of histone marks specifying an active chromatin state for EMT-mediate transcription.

描述（由申请人提供）：已知启动子CpG岛的DNA高甲基化与子宫内膜癌中的转录沉默相关。我们最近鉴定了一组独特的 CpG 岛位点，这些位点在非复发性肿瘤中高度甲基化，但在随后复发的原发性肿瘤中协调地低甲基化（或较少甲基化）。这些位点对 DNA 从头甲基化（即默认状态）高度敏感，部分原因是 DNA 甲基转移酶 1 (DNMT1) 和 Polycomb 阻遏物复合物 2 (PRC2) 的高表达。虽然这些与上皮间质转化（EMT）有关的基因座通常不在正常细胞中表达，但它们的染色质可能保持二价状态，类似于在干细胞和祖细胞中观察到的状态。基于网络的分析将这些位点与表皮生长因子受体 (EGFR) 信号联系起来，表明低 DNA 甲基化特征和允许的染色质状态可以允许通过该途径进行转录激活。我们的功能研究证实了这一点，显示 EGF 通过上皮粘附标记 (EpCAM) 胞内结构域 (EpICD) 诱导候选基因的表达。我们假设 EpICD 转录复合物在靶启动子处的结合限制了 DNMT1/PRC2 进入这些位点，并招募组蛋白甲基转移酶将染色质修饰为复发肿瘤中的活性状态。这种默认状态的表观遗传重写对于 EMT 介导的子宫内膜癌细胞的进展是必要的。在目标 1 中，我们将在子宫内膜癌的独立队列中验证这些候选位点的甲基化状态。这些位点的 DNA 低甲基化和过度表达可用作预测患者子宫内膜癌复发风险的生物标志物。在目标 2 中，我们将评估 EGF 诱导的 EMT 是否导致识别 EpICD 靶基因，描述新的候选低甲基化因子。 EGF诱导细胞的相关间充质特征将通过分子手段和表明侵袭性增加的细胞纳米力学特征进行检查。在目标 3 中，我们将确定 EpICD 转录复合物是否是这种表观遗传重编程的关键因素。 EpICD 与靶启动子的结合预计会减少 DNMT1/PRC2 的结合，并改变组蛋白标记的组合模式，从而指定 EMT 介导转录的活性染色质状态。