Mdig gene and histone demethylation in lung cancer

肺癌中的 Mdig 基因和组蛋白去甲基化

基本信息

批准号：
8427387
负责人：
Fei Chen
金额：
$ 29.56万
依托单位：
WAYNE STATE UNIVERSITY
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：
2009-05-01 至 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8427387
关键词：
A549 Accounting Acute Promyelocytic Leukemia Affect Alveolar Macrophages American Area Biological Assay Biological Markers Carcinogens Cell Culture Techniques Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Line Cell Proliferation Cells Cessation of life Characteristics Cyclins Disease Down-Regulation Dust Environmental Carcinogens Environmental Hazards Environmental and Occupational Exposure Epigenetic Process Epithelial Cells Experimental Models Exposure to Gene Activation Gene Expression Gene Expression Regulation Genes Genome Goals HL-60 Cells Health Heterochromatin Histone H3 Histones Human In Vitro Intervention Knockout Mice Lung Lung diseases Lysine Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Mediator of activation protein Methylation Minerals Molecular Names Nuclear Antigens Nucleolar Proteins Nucleosomes Nude Mice Occupational Oncogene Activation Outcome Patients Peptides Phase Transition Play Prevention strategy Principal Investigator Prognostic Marker Proteins Regimen Regulation Role S Phase Signal Transduction Small Interfering RNA Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Stream Testing Tobacco smoking United States Xenopus laevis attenuation base cancer therapy cancer type cdc Genes cell growth cell growth regulation cell transformation demethylation epigenetic marker expectation improved insight killings loss of function lung cancer screening lung carcinogenesis mass spectrometer mortality novel therapeutic intervention novel therapeutics occupational hazard outcome forecast response small hairpin RNA therapeutic target tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the most common cancer worldwide, accounting for 1.3 million cancer deaths annually. Despite extensive efforts to elucidate mechanisms and develop new therapeutic regimens, the worldwide mortality rate of lung cancer remains high. Our long- term goal is to understand how mdig gene contributes to the initiation and progression of the human lung cancer and whether mdig can be served as a biomarker and a therapeutic target for lung cancer resulted from exposure to environmental or occupational hazards. The objective of this application is to investigate the role of Mdig protein played on the lung cell proliferation and carcinogenic transformation induced by environmental and occupational hazards/carcinogens. The central hypothesis is that Mdig promotes cell growth and transformation by functioning as a histone demethylase that antagonizes tri-methyl lysine 9 on histone H3. Down-regulation of tri-methyl lysine 9 of histone H3 will enhance the expression of genes associated with the cell cycle regulation and malignant transformation in lung epithelial cells. The rationale behind this proposal is that expression of mdig gene may be critical for lung cell proliferation and carcinogenic transformation in response to environmental carcinogens. To accomplish the objectives of this application, we will pursue three specific aims by using cell lines and nude mice as experimental models: (1) test the potential demethylase activity of mdig protein toward tri-methylated lysine 9 on histone H3; (2) determine whether the expression of the cell cycle-regulated genes, such as cyclins, Cdc25s and checkpoint proteins, is regulated by the methylation regulation of mdig; and (3) study the tumorigenic effect of mdig by both over- expression and down-regulation of mdig in BEAS-2B cells and A549 cells, respectively, in both cell culture and inoculation of the cells in nude mice. At the completion of these specific aims, we expect to have determined how mdig contributes to lung cell growth regulation and carcinogenic transformation in response to factors that cause lung cancer. We additionally expect, based on preliminary studies, that constitutive expression of mdig will compromise the tri-methylation of lysine 9 on histone H3, leading to attenuation of heterochromatin or the formation of other inhibitory epigenetic markers. As a result, the expression of genes associated with the cell cycle transition and cell proliferation will be enhanced. Finally, in addition to reveal a previously unknown new mechanism of the human lung cancer, it is anticipated that expression of mdig can be potentially served as a new biomarker and therapeutic target of the human lung cancer.

描述（由申请人提供）：肺癌是全球最常见的癌症，每年占130万个癌症死亡。尽管为阐明机制和开发新的治疗方案而进行了广泛的努力，但肺癌的全球死亡率仍然很高。我们的长期目标是了解MDIG基因如何促进人类肺癌的开始和发展，以及MDIG是否可以用作生物标志物，以及暴露于环境或职业危害的肺癌的治疗靶标。该应用的目的是研究通过环境和职业危害/致癌物诱导的MDIG蛋白在肺部细胞增殖和致癌转化中的作用。中心假设是MDIG通过作为组蛋白脱甲基酶发挥作用，促进细胞的生长和转化，该脱甲基酶在组蛋白H3上拮抗三甲基赖氨酸9。组蛋白H3的三甲基赖氨酸9的下调将增强与细胞周期调节和肺上皮细胞中恶性转化相关的基因的表达。该提议背后的理由是，响应环境致癌物的肺部细胞增殖和致癌转化可能至关重要。为了实现此应用的目标，我们将通过使用细胞系和裸小鼠作为实验模型来追求三个特定目标：（1）测试MDIG蛋白在组蛋白H3上对三甲基化赖氨酸9的潜在脱甲基酶活性；（2）确定细胞周期调节的基因的表达（例如细胞周期蛋白，Cdc25s和检查点蛋白）是否受MDIG的甲基化调节调节；（3）分别研究MDIG在BEAS-2B细胞和A549细胞中MDIG的过度表达和下调的肿瘤效应，分别在细胞培养和裸鼠细胞的接种中。在完成这些特定目标时，我们希望确定MDIG如何促进肺细胞生长调节和致癌性转化，以响应导致肺癌的因素。我们还期望根据初步研究，MDIG的本构表达将损害组蛋白H3上赖氨酸9的三甲基化，从而导致异染色质的衰减或其他抑制性表观遗传标记的形成。结果，将增强与细胞周期过渡和细胞增殖相关的基因的表达。最后，除了揭示了人类肺癌的先前未知的新机制外，还可以预期MDIG的表达可以成为人类肺癌的新生物标志物和治疗靶标。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gefitinib resistance resulted from STAT3-mediated Akt activation in lung cancer cells.

DOI：
10.18632/oncotarget.1431
发表时间：
2013-12
期刊：
Oncotarget
影响因子：
0
作者：
Wu K;Chang Q;Lu Y;Qiu P;Chen B;Thakur C;Sun J;Li L;Kowluru A;Chen F
通讯作者：
Chen F

Reactive oxygen species contribute to arsenic-induced EZH2 phosphorylation in human bronchial epithelial cells and lung cancer cells.

DOI：
10.1016/j.taap.2014.02.005
发表时间：
2014-05-01
期刊：
TOXICOLOGY AND APPLIED PHARMACOLOGY
影响因子：
3.8
作者：
Li, Lingzhi;Qiu, Ping;Chen, Bailing;Lu, Yongju;Wu, Kai;Thakur, Chitra;Chang, Qingshan;Sun, Jiaying;Chen, Fei
通讯作者：
Chen, Fei

Increased expression of mdig predicts poorer survival of the breast cancer patients.