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: 9295840
• 负责人: Steven A Belinsky
• 金额: $ 77.87万
• 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/9295840
• 关键词: Affect; Animal Model; Automobile Driving; Biological Markers; Cancer Etiology; Cancer Model; 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; Dose; EZH2 gene; Effectiveness; Environmental Tobacco Smoke; Epigenetic Process; Epithelial Cells; Evolution; Exposure to; Gene Chips; Gene Expression; Gene Silencing; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Heterochromatin; Histone Deacetylase; Histone H3; Human; In Vitro; Injury; Intervention; Knowledge; Lead; Lesion; Lung; Mainstreaming; Malignant - descriptor; 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; Pharmacology; Phenotype; Placebos; Premalignant; Prevention; Prevention strategy; Prevention trial; Preventive; Preventive Intervention; Primary Neoplasm; Primary Prevention; Process; Proteins; Randomized; Serum; Smoker; Smoking; Sputum; Testing; 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; disease heterogeneity; early detection biomarkers; epigenome; epithelial to mesenchymal transition; exposed human population; fatty acid supplementation; gene repression; genome-wide; genotoxicity; histone methyltransferase; in vitro Model; in vivo; inhibitor/antagonist; innovation; insight; knock-down; lung cancer prevention; mortality; neoplastic; never smoker; novel; overexpression; predicting response; predictive marker; prevent; programs; promoter; public health relevance; response; response biomarker; small molecule inhibitor; smoking cessation; therapeutic biomarker; 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）：肺癌新靶向和化疗的发展，虽然在晚期肺癌的中位生存期方面取得了一定的改善，但没有提供明确的药物途径，使这种疾病成为一种慢性疾病，就像今天的转移性乳腺癌一样。虽然戒烟可以降低死亡率，但 50% 的肺癌病例是在以前吸烟者中诊断出来的，因此需要有效的预防药物。开发肺癌预防药物也具有挑战性，因为这种疾病在遗传和表观遗传改变方面具有异质性，并且缺乏替代组织来非侵入性地询问治疗效果反应的中间生物标志物。二十多年来，我们的团队一直致力于了解肺癌病因、开发和验证用于早期检测的生物标志物，以及评估动物模型中治疗和预防干预措施的功效。令人兴奋的是，基因表达变化的损伤范围从肺部延伸到鼻上皮，这为通过评估预测鼻上皮反应的生物标志物来评估新型一级预防策略的有效性提供了新的机会。我们的烟草致癌物诱导的人支气管上皮细胞（HBEC）转化的体外模型为导致癌前病变的最早步骤和目标提供了重要的新见解。其中最显着的是调节上皮间质转化的 microRNA 的转录抑制，以及首先由 EZH2 和/或 G9a 催化的染色质重塑介导的肿瘤抑制基因的沉默，以及随后在恶性肿瘤进展过程中的密集从头 DNA 甲基化。由染色质重塑和胞嘧啶甲基化介导的表观遗传沉默影响数百个基因，这些基因可能驱动癌前上皮细胞的起始和克隆生长，从而导致恶性肿瘤。这些发现以及染色质重塑可以用非基因毒性药物逆转的事实（与胞嘧啶-DNA 甲基化不同，胞嘧啶 DNA 甲基化需要用基因毒性胞苷类似物处理才能实现强力去甲基化），为测试预防性干预措施提供了令人兴奋的新机会，重点是诱导这些表观遗传的重新表达反过来，这些受调控的基因应该能够阻止或逆转癌前病变。本申请中的三个综合具体目标将首先使用 HBEC 模型来定义调节这些癌症相关组蛋白甲基转移酶的表达对其基因靶标和转化过程的影响，从而推进这些发现。其次，我们将评估饮食、药理学和/或 EZH2 和 G9a 的特异性小分子抑制剂是否可以减轻这些基因靶点的转录抑制和体外转化，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转化，该研究的重点是评估前吸烟者补充欧米伽脂肪酸是否可以调节鼻上皮中 EZH2 调节基因的表达谱，这些基因在 HBEC 转化过程中发生改变。