Abstract
Lung cancer is the leading cause of cancer-related deaths in the world. Achaete-scute complex homolog-1 (Ascl1) is a member of the basic helix-loop-helix (bHLH) transcription factor family that has multiple functions in the normal and neoplastic lung such as the regulation of neuroendocrine differentiation, prevention of apoptosis and promotion of tumor-initiating cells. We now show that Ascl1 directly regulates matrix metalloproteinase-7 (MMP-7) and O(6)-methylguanine-DNA methyltransferase (MGMT). Loss- and gain-of-function experiments in human bronchial epithelial and lung carcinoma cell lines revealed that Ascl1, MMP-7 and MGMT are able to protect cells from the tobacco-specific nitrosamine NNK-induced DNA damage and the alkylating agent cisplatin-induced apoptosis. We also examined the role of Ascl1 in NNK-induced lung tumorigenesis in vivo. Using transgenic mice which constitutively expressed human Ascl1 in airway lining cells, we found that there was a delay in lung tumorigenesis. We conclude that Ascl1 potentially enhances DNA repair through activation of MMP-7 and MGMT which may impact lung carcinogenesis and chemoresistance. The study has uncovered a novel and unexpected function of Ascl1 which will contribute to better understanding of lung carcinogenesis and the broad implications of transcription factors in tobacco-related carcinogenesis.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Adenoma / chemically induced
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Adenoma / metabolism
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Animals
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Antineoplastic Agents, Alkylating / pharmacology
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Apoptosis / drug effects
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Basic Helix-Loop-Helix Transcription Factors / physiology*
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Cell Line, Tumor
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Cell Transformation, Neoplastic / chemically induced
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Cell Transformation, Neoplastic / metabolism
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Cisplatin / pharmacology
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DNA Damage
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DNA Modification Methylases / genetics
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DNA Modification Methylases / metabolism*
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DNA Repair Enzymes / genetics
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DNA Repair Enzymes / metabolism*
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DNA Repair*
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Enzyme Induction
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Gene Expression Regulation, Neoplastic
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Gene Knockdown Techniques
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Humans
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Lung Neoplasms / chemically induced
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Lung Neoplasms / metabolism*
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Matrix Metalloproteinase 7 / genetics
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Matrix Metalloproteinase 7 / metabolism*
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Mice
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Mice, Transgenic
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Nitrosamines
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Promoter Regions, Genetic
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Protein Binding
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RNA, Small Interfering / genetics
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Small Cell Lung Carcinoma / metabolism*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Up-Regulation
Substances
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ASCL1 protein, human
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Antineoplastic Agents, Alkylating
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Basic Helix-Loop-Helix Transcription Factors
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Nitrosamines
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RNA, Small Interfering
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Tumor Suppressor Proteins
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4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
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DNA Modification Methylases
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MGMT protein, human
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MMP7 protein, human
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Matrix Metalloproteinase 7
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DNA Repair Enzymes
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Cisplatin