title: GATA3 interacts with and stabilizes HIF-1α to enhance cancer cell invasiveness.
abstract: GATA binding protein 3 (GATA3) is indispensable in development of human organs. However, the role of GATA3 in cancers remains elusive. Hypoxia inducible factor (HIF)-1 plays an important role in pathogenesis of human cancers. Regulation of HIF-1α degradation is orchestrated through collaboration of its interacting proteins. In this study, we discover that GATA3 is upregulated in head and neck squamous cell carcinoma (HNSCC) and is an independent predictor for poor disease-free survival. GATA3 promotes invasive behaviours of HNSCC and melanoma cells in vitro and in immunodeficient mice. Mechanistically, GATA3 physically associates with HIF-1α under hypoxia to inhibit ubiquitination and proteasomal degradation of HIF-1α, which is independent of HIF-1α prolyl hydroxylation. Chromatin immunoprecipitation assays show that the GATA3/HIF-1α complex binds to and regulates HIF-1 target genes, which is also supported by the microarray analysis. Notably, the GATA3-mediated invasiveness can be significantly reversed by HIF-1α knockdown, suggesting a critical role of HIF-1α in the underlying mechanism of GATA3-mediated effects. Our findings suggest that GATA3 stabilizes HIF-1α to enhance cancer invasiveness under hypoxia and support the GATA3/HIF-1α axis as a potential therapeutic target for cancer treatment.
authors.affiliation: Department of Otolaryngology, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu City, Taiwan.|Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: M-C
authors.initials: MC
authors.lastname: Lin
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Lin
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: C-L
authors.initials: CL
authors.lastname: Hsu
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: H-F
authors.initials: HF
authors.lastname: Juan
authors.affiliation: Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan.|Department of Otolaryngology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
authors.forename: P-J
authors.initials: PJ
authors.lastname: Lou
authors.affiliation: Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: M-C
authors.initials: MC
authors.lastname: Huang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia; D047369:Chromatin Immunoprecipitation; D005260:Female; D050990:GATA3 Transcription Factor / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit