Histone Methyltransferases as a Target for Lung Cancer Prevention

组蛋白甲基转移酶作为肺癌预防的靶点

• 批准号: 8856526
• 负责人: Steven A Belinsky
• 金额: $ 58.15万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8856526
• 关键词: Affect; Animal Model; Automobile Driving; Biological Markers; Cancer Etiology; Cancer Model; Cancer Prevention Trial; Carcinogen exposure; Carcinogens; Cell Line; Cell model; Cells; ChIP-on-chip; ChIP-seq; Chromatin; Chronic Disease; CpG Islands; Cytidine; Cytosine; DNA Methylation; DNA Modification Methylases; DNA Repair; Development; Diagnosis; Diet; Disease; Dose; EZH2 gene; Early Diagnosis; Effectiveness; Environmental Tobacco Smoke; Epigenetic Process; Epithelial Cells; Evolution; Exposure to; Fatty Acids; Gene Expression; Gene Silencing; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Health; Heterochromatin; Heterogeneity; Histone H3; Histones; Human; In Vitro; Injury; Intervention; Knowledge; Lead; Lesion; Lung; Mainstreaming; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metastatic breast cancer; Methylation; MicroRNAs; Molecular; Molecular Profiling; Mus; N-3 polyunsaturated fatty acid; Nasal Epithelium; Neoplasms; Nose; Omega-3 Fatty Acids; Pharmaceutical Preparations; Placebos; Premalignant; Prevention; Prevention strategy; Prevention trial; Preventive; Preventive Intervention; Primary Neoplasm; Primary Prevention; Process; Proteins; Randomized; Serum; Smoker; Smoking; Sputum; Supplementation; Testing; Therapeutic Intervention; Tissues; Tobacco-Associated Carcinogen; Translating; Treatment Efficacy; Tumor Suppressor Genes; Tumor-Derived; Work; analog; base; bronchial epithelium; cancer risk; chemotherapy; chromatin remodeling; cohort; demethylation; dietary supplements; epigenome; epithelial to mesenchymal transition; gene repression; genome-wide; histone methyltransferase; in vitro Model; in vivo; inhibitor/antagonist; innovation; insight; knock-down; lung cancer prevention; malignant phenotype; mortality; neoplastic; never smoker; novel; prevent; programs; promoter; response; small molecule; smoking cessation; tumor

DESCRIPTION (provided by applicant): The evolution of new targeted and chemotherapies for lung cancer, while achieving modest improvement in median survival for advanced lung cancer, offer no clear path to drugs that could make this a chronic disease as seen today for metastatic breast cancer. While smoking cessation reduces mortality, 50% of lung cancer cases are diagnosed in former smokers, necessitating the need for effective preventive agents. Developing lung cancer preventive drugs has also been challenging because of the heterogeneity of this disease with respect to genetic and epigenetic alterations and the lack of a surrogate tissue to noninvasively interrogate intermediate biomarkers of response for therapeutic efficacy. Our group has focused for more than two decades on understanding lung cancer etiology, developing and validating biomarkers for early detection, and assessing efficacy of interventions for therapy and prevention in animal models. The exciting realization that the field of injury extends from the lungs to the nasal epithelium for gene expression changes provides new opportunities to evaluate the effectiveness of novel primary prevention strategies by assessing biomarkers predictive of response in the nasal epithelium. Our tobacco carcinogen-induced in vitro model for transformation of human bronchial epithelial cells (HBECs) has provided key new insights into the earliest steps and targets contributing to pre-malignancy. They include most notably transcriptional repression of microRNAs regulating epithelial to mesenchymal transition and silencing of tumor suppressor genes mediated first by chromatin remodeling catalyzed by either EZH2 and/or G9a, with subsequent dense de novo DNA methylation during progression to malignancy. Epigenetic silencing mediated by chromatin remodeling and cytosine methylation affects hundreds of genes that likely drive initiation and clonal outgrowth of premalignant epithelial cells leading to malignancy. These discoveries and fact that chromatin remodeling can be reversed with non-genotoxic agents (unlike cytosine-DNA methylation which requires treatment with genotoxic cytidine analogs for robust demethylation) offer exciting new opportunities to test preventive interventions focused on inducing the re-expression of these epigenetically regulated genes that in turn, should impede or reverse pre- malignancy. The three integrated specific aims in this application will advance these discoveries by first using the HBEC model to define the effect of modulating the expression of these cancer-associated histone methyltransferases on their gene targets and the transformation process. Second, we will assess whether diet, pharmacologic, and/or specific small molecule inhibitors to EZH2 and G9a can mitigate the transcriptional repression at these gene targets and transformation in vitro and prevent tumor development in vivo. Finally, this work will be translated through a prevention study focused on evaluating whether omega fatty acid supplementation in former smokers can modulate the expression profile in nasal epithelium of EZH2 regulated genes that are altered during transformation of HBECs.

描述（由申请人提供）：肺癌的新靶向和化学疗法的演变，同时实现晚期肺癌中位生存率的适度改善，没有明显的药物途径，可以使这种慢性疾病成为今天的转移性乳腺癌的慢性疾病。尽管戒烟降低了死亡率，但在以前的吸烟者中诊断出50％的肺癌病例，因此需要有效的预防剂。由于这种疾病在遗传和表观遗传改变以及缺乏替代组织来无创询问治疗功效的反应中间生物标志物方面，这种疾病的异质性异质，因此发展肺癌的预防药物也在具有挑战性。我们的小组一直关注二十年来，了解肺癌的病因，开发和验证生物标志物以早期检测以及评估动物模型中治疗和预防的干预措施的功效。令人兴奋的意识到，损伤领域从肺部延伸到鼻上皮，用于基因表达变化，这为您通过评估鼻上皮中反应的生物标志物来评估新的原发性预防策略的有效性提供了新的机会。我们的烟癌致癌诱导的体外模型，用于转化人支气管上皮细胞（HBEC），为最早的步骤和目标提供了关键的新见解，从而有助于预防前。其中包括对调节上皮过渡到间充质转变的microRNA的转录抑制以及对EZH2和/或G9A催化的染色质重塑介导的肿瘤抑制基因的沉默，并随后在进展为恶化期间具有随后的De Nove De Novo DNA甲基化。染色质重塑和胞嘧啶甲基化介导的表观遗传沉默会影响数百个基因，这些基因可能会驱动启动的起始和上皮细胞的克隆生长，从而导致恶性肿瘤。 These discoveries and fact that chromatin remodeling can be reversed with non-genotoxic agents (unlike cytosine-DNA methylation which requires treatment with genotoxic cytidine analogs for robust demethylation) offer exciting new opportunities to test preventive interventions focused on inducing the re-expression of these epigenetically regulated genes that in turn, should impede or reverse pre- malignancy.该应用程序中的三个集成特定目标将通过首先使用HBEC模型来定义调节这些与癌症相关的组蛋白甲基转移酶对其基因靶标和转化过程的表达的效果。其次，我们将评估EZH2和G9A对EZH2和G9A的饮食，药理和/或特定的小分子抑制剂是否可以减轻这些基因靶标的转录抑制作用，并在体外转化并预防体内肿瘤的发展。最后，这项工作将通过一项预防研究来翻译，该研究的重点是评估以前吸烟者中补充欧米茄脂肪酸是否可以调节EZH2调节基因的鼻皮上表达谱，这些基因在HBEC转化过程中发生了改变。