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.

Public Health Relevance

Lung cancer is the leading cause of malignant-related deaths in the United States (US). It kills more Americans than any other type of malignancy. The main cause of lung cancer is the environmental and occupational exposure to carcinogens, including tobacco smoking and occupational dust. This project will investigate the mechanism of mdig gene, a newly identified lung cancer associated gene, in mediating carcinogen-induced lung cancer by testing the hypothesis that mdig inducing cell growth and transformation through down regulation of the tri-methylation of lysine 9 on histone H3 and the heterochromatin formation. The long-term goals are to understand how mdig gene contributes to the initiation and progression of the human lung cancer induced by environmental and occupational hazards, to identify biomarkers for early detection of the lung cancer and to develop intervention and prevention strategies.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Reinlib, Leslie J
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Wayne State University
Schools of Pharmacy
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Thakur, Chitra; Chen, Bailing; Li, Lingzhi et al. (2018) Loss of mdig expression enhances DNA and histone methylation and metastasis of aggressive breast cancer. Signal Transduct Target Ther 3:25
Li, Lingzhi; Chen, Fei (2016) Oxidative stress, epigenetics, and cancer stem cells in arsenic carcinogenesis and prevention. Curr Pharmacol Rep 2:57-63
Wu, Kai; Li, Lingzhi; Thakur, Chitra et al. (2016) Proteomic Characterization of the World Trade Center dust-activated mdig and c-myc signaling circuit linked to multiple myeloma. Sci Rep 6:36305
Thakur, Chitra; Chen, Fei (2015) Current understanding of mdig/MINA in human cancers. Genes Cancer 6:288-302
Wang, Wei; Lu, Yongju; Stemmer, Paul M et al. (2015) The proteomic investigation reveals interaction of mdig protein with the machinery of DNA double-strand break repair. Oncotarget 6:28269-81
Li, Lingzhi; Lu, Yongju; Stemmer, Paul M et al. (2015) Filamin A phosphorylation by Akt promotes cell migration in response to arsenic. Oncotarget 6:12009-19
Thakur, Chitra; Wolfarth, Michael; Sun, Jiaying et al. (2015) Oncoprotein mdig contributes to silica-induced pulmonary fibrosis by altering balance between Th17 and Treg T cells. Oncotarget 6:3722-36
Chang, Qingshan; Chen, Bailing; Thakur, Chitra et al. (2014) Arsenic-induced sub-lethal stress reprograms human bronchial epithelial cells to CD61¯ cancer stem cells. Oncotarget 5:1290-303
Thakur, Chitra; Lu, Yongju; Sun, Jiaying et al. (2014) Increased expression of mdig predicts poorer survival of the breast cancer patients. Gene 535:218-24
Li, Lingzhi; Qiu, Ping; Chen, Bailing et al. (2014) Reactive oxygen species contribute to arsenic-induced EZH2 phosphorylation in human bronchial epithelial cells and lung cancer cells. Toxicol Appl Pharmacol 276:165-70

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