GATA3 interacts with and stabilizes HIF-1α to enhance cancer cell invasiveness
Journal
Oncogene
Journal Volume
36
Journal Issue
30
Pages
4243-4252
Date Issued
2017
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. ? 2017 The Author(s).
SDGs
Other Subjects
hypoxia inducible factor 1alpha; transcription factor GATA 3; GATA3 protein, human; HIF1A protein, human; hypoxia inducible factor 1alpha; transcription factor GATA 3; adult; animal experiment; animal model; animal tissue; Article; chromatin immunoprecipitation; complex formation; disease free survival; female; gene; head and neck squamous cell carcinoma; human; human tissue; hydroxylation; in vitro study; male; melanoma cell; microarray analysis; middle aged; mouse; nonhuman; priority journal; protein degradation; protein protein interaction; protein stability; tumor invasion; ubiquitination; upregulation; animal; cell hypoxia; gene expression regulation; head and neck tumor; immunohistochemistry; immunoprecipitation; metabolism; nonobese diabetic mouse; pathology; physiology; real time polymerase chain reaction; SCID mouse; squamous cell carcinoma; tumor invasion; Western blotting; xenograft; Animals; Blotting, Western; Carcinoma, Squamous Cell; Cell Hypoxia; Chromatin Immunoprecipitation; Female; GATA3 Transcription Factor; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Heterografts; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Immunoprecipitation; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Invasiveness; Real-Time Polymerase Chain Reaction
Publisher
Nature Publishing Group
Type
journal article