title: Hypoxia induces CD133 expression in human lung cancer cells by up-regulation             of OCT3/4 and SOX2.
abstract: CD133 has been recognized as a specific cell surface marker for cancer stem             cells in various tumors, although its biological functions and transcriptional             regulation remain unclear. We found that the CD133 expression level was up-regulated             in the lung cancer cell lines N417, H358, and A549, when these cell lines were             cultured under hypoxic conditions. Among the five promoters (P1-P5) of human CD133             gene loci, P1 promoter was most strongly associated with hypoxia-induced promoter             activity of CD133 gene expression. The P1 promoter possesses several cis-regulatory             elements, including RUNT, GATA, ETS, OCT, SRY, and CREB-binding sites. A series             of deletion and base substitution mutants of the P1 promoter revealed that OCT-             and SRY-binding sites are important for hypoxia-induced promoter activity. The             chromatin immunoprecipitation assay further confirmed the direct binding of Octamer             biding trans-cription factor 3/4 (OCT4) and/or SRY-box containing gene 2 (SOX2)             to the P1 promoter region of CD133 gene loci. In addition, the enhancement of             both OCT4 and SOX2 expression by the α subunit of hypoxia-inducible factors (HIF1α             and HIF2α) was required for hypoxia-induced CD133 expression. Knockdown of OCT4             or SOX2 expression in N417 cells with stabilized HIF1α and/or HIF2α abolished             CD133P1 activity, while ectopic OCT4 or SOX2 expression triggers CD133P1 activity             in the absence of HIF1α or HIF2α. Thus, in the hypoxic conditions, OCT4 and SOX2,             both of which are induced by HIF1α/HIF2α. promote CD133 expression in the lung             cancer cells via their direct interaction with the P1 promoter.
authors.affiliation: Department of Biochemistry, University of Occupational and Environmental                     Health, Fukuoka, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Iida
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Suzuki
authors.forename: Ryo
authors.initials: R
authors.lastname: Goitsuka
authors.forename: Hikaru
authors.initials: H
authors.lastname: Ueno
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis* / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D010455:Peptides / Q000235:genetics; D011401:Promoter Regions, Genetic; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation; D000099254:Organic Cation Transporter 3
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050814:Octamer Transcription Factor-3; D027701:Organic Cation Transport Proteins; D010455:Peptides; D055748:SOXB1 Transcription Factors; D000099254:Organic Cation Transporter 3; C497442:HIF1A protein, human; C494173:POU5F1 protein, human; C000606023:PROM1 protein, human; C527782:SOX2 protein, human