title: Achaete-scute complex homolog-1 promotes DNA repair in the lung carcinogenesis through matrix metalloproteinase-7 and O(6)-methylguanine-DNA methyltransferase.
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.
authors.affiliation: Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America. xiaoyangwang@gmail.com
authors.forename: Xiao-Yang
authors.initials: XY
authors.lastname: Wang
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Jensen-Taubman
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Keefe
authors.forename: Danlei
authors.initials: D
authors.lastname: Yang
authors.forename: R Ilona
authors.initials: RI
authors.lastname: Linnoila
mesh_terms: D000236:Adenoma / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009602:Nitrosamines; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D055752:Small Cell Lung Carcinoma / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018906:Antineoplastic Agents, Alkylating; D051792:Basic Helix-Loop-Helix Proteins; D002945:Cisplatin; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D020783:Matrix Metalloproteinase 7; D009602:Nitrosamines; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C065500:ASCL1 protein, human; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C515491:MGMT protein, human; C060932:MMP7 protein, human