title: Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype.
abstract: Intratumoral hypoxia, which is associated with breast cancer metastasis and patient mortality, increases the percentage of breast cancer stem cells (BCSCs) but the underlying molecular mechanisms have not been delineated. Here we report that hypoxia-inducible factor 1 (HIF-1) triggers the expression and activity of TAZ, a transcriptional co-activator that is required for BCSC maintenance, through two discrete mechanisms. First, HIF-1 binds directly to the WWTR1 gene and activates transcription of TAZ mRNA. Second, HIF-1 activates transcription of the SIAH1 gene, which encodes a ubiquitin protein ligase that is required for the hypoxia-induced ubiquitination and proteasome-dependent degradation of LATS2, a kinase that inhibits the nuclear localization of TAZ. Inhibition of HIF-1α, TAZ, or SIAH1 expression by short hairpin RNA blocked the enrichment of BCSCs in response to hypoxia. Human breast cancer database analysis revealed that increased expression (greater than the median) of both TAZ and HIF-1 target genes, but neither one alone, is associated with significantly increased patient mortality. Taken together, these results establish a molecular mechanism for induction of the BCSC phenotype in response to hypoxia.
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China. Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Lisha
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Daniele M
authors.initials: DM
authors.lastname: Gilkes
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Hu
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Naoharu
authors.initials: N
authors.lastname: Takano
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Weibo
authors.initials: W
authors.lastname: Luo
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Haiquan
authors.initials: H
authors.lastname: Lu
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: John W
authors.initials: JW
authors.lastname: Bullen
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Debangshu
authors.initials: D
authors.lastname: Samanta
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Houjie
authors.initials: H
authors.lastname: Liang
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000217:Acyltransferases; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D064593:Heterografts; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051793:Hypoxia-Inducible Factor 1; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases