title: KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer.
abstract: Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. To identify novel factors that contribute to lung cancer pathogenesis, we analyzed a lung cancer database from The Cancer Genome Atlas and found that Krüppel-like Factor 4 (KLF4) expression is significantly lower in patients' lung cancer tissue than in normal lung tissue. In addition, we identified seven missense mutations in the KLF4 gene. KLF4 is a transcription factor that regulates cell proliferation and differentiation as well as the self-renewal of stem cells. To understand the role of KLF4 in the lung, we generated a tamoxifen-induced Klf4 knockout mouse model. We found that KLF4 inhibits lung cancer cell growth and that depletion of Klf4 altered the differentiation pattern in the developing lung. To understand how KLF4 functions during lung tumorigenesis, we generated the K-ras(LSL-G12D/+);Klf4(fl/fl) mouse model, and we used adenovirus-expressed Cre to induce K-ras activation and Klf4 depletion in the lung. Although Klf4 deletion alone or K-ras mutation alone can trigger lung tumor formation, Klf4 deletion combined with K-ras mutation significantly enhanced lung tumor formation. We also found that Klf4 deletion in conjunction with K-ras activation caused lung inflammation. To understand the mechanism whereby KLF4 is regulated during lung tumorigenesis, we analyzed KLF4 promoter methylation and the profiles of epigenetic factors. We found that Class I histone deacetylases (HDACs) are overexpressed in lung cancer and that HDAC inhibitors induced expression of KLF4 and inhibited proliferation of lung cancer cells, suggesting that KLF4 is probably repressed by histone acetylation and that HDACs are valuable drug targets for lung cancer treatment.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40506-0509, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY 40506-0509, USA.
authors.forename: T
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40506-0509, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY 40506-0509, USA.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40506-0509, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY 40506-0509, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40506-0509, USA.|Department of Biostatistics, University of Kentucky, Lexington, KY 40506-0509, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY 40506-0509, USA.
authors.forename: R
authors.initials: R
authors.lastname: Avdiushko
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40506-0509, USA.|Department of Pathology, University of Kentucky, Lexington, KY 40506-0509, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Napier
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40506-0509, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY 40506-0509, USA.
authors.forename: A X
authors.initials: AX
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Kentucky, Lexington, KY 40506-0509, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Neltner
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40506-0509, USA.|Department of Biostatistics, University of Kentucky, Lexington, KY 40506-0509, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY 40506-0509, USA.
authors.forename: D
authors.initials: D
authors.lastname: Cohen
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40506-0509, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY 40506-0509, USA.
authors.forename: C
authors.initials: C
authors.lastname: Liu
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D014411:Neoplastic Stem Cells / Q000502:physiology*; D011401:Promoter Regions, Genetic; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000502:physiology
chemical_list: D056572:Histone Deacetylase Inhibitors; C000715467:KLF4 protein, human; C117307:KRAS protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D025521:Tumor Suppressor Proteins; D016283:Proto-Oncogene Proteins p21(ras)