title: Bmi1 regulates cell fate via tumor suppressor WWOX repression in small-cell lung cancer cells.
abstract: Mortality from lung cancer is important worldwide. Recently, epigenetic aberration of lung cancer, not only genomic DNA methylation but also chromatin modification, has become an important target for lung cancer research, although previous research has demonstrated that lung cancer develops as a result of both environmental and genetic factors. Here, we demonstrated that an epigenetic regulator/polycomb group protein Bmi1 is more highly expressed in small-cell lung cancer (SCLC) than in non-small-cell lung cancer by immunohistochemical analysis. In vitro experiments indicated that Bmi1 reduction by lentivirus-derived shRNA significantly suppressed proliferation, colony formation and in vivo tumor formation. Importantly, apoptosis was induced by Bmi1 depletion in small-cell lung cancer cells. Furthermore, a tumor suppressor WWOX was identified as a Bmi1 target in the cells by a chromatin immunoprecipitation assay and a quantitative real-time PCR assay; WWOX had a role as a tumor suppressor in SCLC cells; therefore, the Bmi1/WWOX pathway could be a new candidate for a new therapeutic approach for SCLC.
authors.affiliation: Division of Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kimura
authors.forename: Hisanori
authors.initials: H
authors.lastname: Takenobu
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Akita
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nakazawa
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Ochiai
authors.forename: Osamu
authors.initials: O
authors.lastname: Shimozato
authors.forename: Yu-ichi
authors.initials: Y
authors.lastname: Fujimura
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yoshino
authors.forename: Hideki
authors.initials: H
authors.lastname: Kimura
authors.forename: Akira
authors.initials: A
authors.lastname: Nakagawara
authors.forename: Takehiko
authors.initials: T
authors.lastname: Kamijo
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor; D019070:Cell Lineage; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: C069077:BMI1 protein, human; D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; D063150:Polycomb Repressive Complex 1