ROLE OF DNA METHYLTRANSFERASE 3B IN LUNG TUMORIGENESIS

DNA 甲基转移酶 3B 在肺肿瘤发生中的作用

基本信息

批准号：
8261869
负责人：
LI MAO
金额：
$ 30.19万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-07 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8261869
关键词：
Aberrant DNA Methylation Adult Age Amino Acids Animal Model Animals Biologic Characteristic Biological Biology Bronchogenic Carcinoma C-terminal Cancer Etiology Cancer cell line Cessation of life Chromatin Clinical CpG Islands DNA DNA Binding DNA Methylation DNA Methylation Regulation DNA Methyltransferase DNA Methyltransferase 3B DNA Microarray Chip DNA Modification Methylases Data Developed Countries Development Disease Epigenetic Process Epithelial Epithelial Cells Future Gene Expression Profile Genes Genetic Transcription Genomic Instability Goals Health Human Human Genome Knowledge Lead Lesion MCAM gene Malignant Neoplasms Malignant neoplasm of lung Methylation Methyltransferase Molecular Profiling Mutation N-terminal Non-Small-Cell Lung Carcinoma Normal Cell Oncogenes Outcome Pattern Play Proliferating Property Protein Binding Domain Proteins Role Sampling Site Specificity Specimen Structure of parenchyma of lung Survival Rate Testing Therapeutic Effect Tissues Transcript Transgenic Animals Transgenic Mice Tumor Suppressor Genes Tumor Tissue United States Variant Woman Work cDNA Library cancer cell cancer prevention cancer therapy cancer type demethylation effective therapy in vivo innovation interest lung tumorigenesis men novel novel diagnostics novel therapeutics promoter protein complex protein protein interaction tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related death among both men and women in the United States and developed countries. More than 163,000 deaths due to lung cancer in the U.S. were estimated in 2007. With an overall 5-year survival rate of less than 15%, novel diagnostic and therapeutic strategies are critically needed; however, limitations in our understanding of the biology of the disease have hampered these efforts. Epigenetic alterations, particularly aberrant DNA methylation, play as important a role as genetic alterations in lung tumorigenesis. Disregulation of DNA methyltransferases, particularly DNMT1 and DNMT3B, has been implicated in the abnormal distribution of DNA methylation patterns in tumorigenesis. We have identified a novel DNMT3B subfamily, DNMT3B, with at least 7 transcriptional variants. We also discovered that a significant portion of lung cancers expressed only DNMT3B lacking the methyltransferase enzymatic domain (DNMT3B-del), suggesting an expanded role of DNMT3B in lung tumorigenesis. We further showed that DNMT3B is the major form of DNMT3B transcription in adult tissues, and that expression patterns of DNMT3B variants are critical for promoter-specific regulation of DNA methylation. Therefore, we hypothesize that DNMT3B plays an essential role in maintaining DNA methylation pattern distributions in the human genome, and that disrupted expression patterns of the DNMT3Bs determine abnormal DNA methylation with promoter-specificity in lung tumorigenesis. We propose 4 specific aims: Aim 1: To correlate expression patterns of DNMT3B and DNMT3B variants to the global and promoter-specific DNA methylation patterns in primary lung cancer specimens; Aim 2: To determine functional differences between DNMT3B and DNMT3B in DNA methylation control and other biological properties; Aim 3: To determine biological properties of the major DNMT3B variants with or without the DNA methyltransferase enzymatic domains; and Aim 4: To determine the causal relationship between DNMT3B variants and DNA methylation patterns in lung tumorigenesis. Our long-term goals are to better understand the role of these aberrant DNA methyltransferases and to apply this knowledge in future novel diagnostic and therapeutic strategies targeting DNA methylation in lung cancer. PUBLIC HEALTH RELEVANCE: We have discovered a novel DNMT3B subfamily, termed DNMT3B with at least 7 variants. We further discovered that a large percent of lung cancers expressed only DNMT3B lacking of the methyltransferase enzymatic domain, suggesting a role of DNMT3B beyond a DNA methyltransferase in lung tumorigenesis. DNMT3B is the major form of DNMT3B transcription in adult tissues and the expression patterns of DNMT3B variants are critical in promoter-specific regulation of DNA methylation of promoters. The hypothesis to be tested here is that DNMT3B plays an essential role in maintaining distribution of DNA methylation patterns in human genome and disrupted expression patterns of the DNMT3Bs determine the abnormal DNA methylation in lung tumorigenesis. The studies proposed in this proposal will allow us understand the role of DNMT3B variants in lung cancer for development of novel diagnostic and therapeutic strategies.

描述（由申请人提供）：肺癌是美国和发达国家男性和女性癌症相关死亡的主要原因。 2007 年，美国估计有超过 163,000 人死于肺癌。由于总体 5 年生存率低于 15%，因此迫切需要新的诊断和治疗策略；然而，我们对该疾病生物学认识的局限性阻碍了这些努力。表观遗传改变，特别是异常 DNA 甲基化，在肺肿瘤发生中与遗传改变一样重要。 DNA 甲基转移酶（特别是 DNMT1 和 DNMT3B）的失调与肿瘤发生中 DNA 甲基化模式的异常分布有关。我们已经鉴定出一个新的 DNMT3B 亚家族 DNMT3B，它至少有 7 个转录变体。我们还发现，很大一部分肺癌仅表达缺乏甲基转移酶酶结构域（DNMT3B-del）的DNMT3B，这表明DNMT3B在肺肿瘤发生中的作用扩大。我们进一步表明，DNMT3B 是成人组织中 DNMT3B 转录的主要形式，并且 DNMT3B 变体的表达模式对于 DNA 甲基化的启动子特异性调节至关重要。因此，我们假设 DNMT3B 在维持人类基因组中 DNA 甲基化模式分布方面发挥着重要作用，并且 DNMT3B 表达模式的破坏决定了肺肿瘤发生中具有启动子特异性的异常 DNA 甲基化。我们提出了 4 个具体目标：目标 1：将 DNMT3B 和 DNMT3B 变体的表达模式与原发性肺癌标本中的整体和启动子特异性 DNA 甲基化模式相关联；目标2：确定DNMT3B和DNMT3B在DNA甲基化控制和其他生物学特性方面的功能差异；目标 3：确定具有或不具有 DNA 甲基转移酶酶促结构域的主要 DNMT3B 变体的生物学特性；目标 4：确定 DNMT3B 变异与肺肿瘤发生中 DNA 甲基化模式之间的因果关系。我们的长期目标是更好地了解这些异常 DNA 甲基转移酶的作用，并将这些知识应用于未来针对肺癌 DNA 甲基化的新型诊断和治疗策略。公共健康相关性：我们发现了一个新的 DNMT3B 亚家族，称为 DNMT3B，具有至少 7 个变体。我们进一步发现，很大一部分肺癌仅表达缺乏甲基转移酶酶结构域的 DNMT3B，这表明 DNMT3B 在肺肿瘤发生中的作用超出了 DNA 甲基转移酶。 DNMT3B 是成人组织中 DNMT3B 转录的主要形式，DNMT3B 变体的表达模式对于启动子 DNA 甲基化的启动子特异性调控至关重要。这里要测试的假设是，DNMT3B 在维持人类基因组中 DNA 甲基化模式的分布中发挥着重要作用，并且 DNMT3B 表达模式的破坏决定了肺部肿瘤发生中的异常 DNA 甲基化。该提案中提出的研究将使我们了解 DNMT3B 变异在肺癌中的作用，以开发新的诊断和治疗策略。