GATA3 interacts with and stabilizes HIF-1[alpha] to enhance cancer cell invasiveness
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-1[alpha] degradation is orchestrated through collaborati...
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| Veröffentlicht in: | Oncogene 2017-07, Vol.36 (30), p.4243 |
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| creator | Lin, M-C Lin, J-J Hsu, C-L Juan, H-F Lou, P-J Huang, M-C |
| description | 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-1[alpha] 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-1[alpha] under hypoxia to inhibit ubiquitination and proteasomal degradation of HIF-1[alpha], which is independent of HIF-1[alpha] prolyl hydroxylation. Chromatin immunoprecipitation assays show that the GATA3/HIF-1[alpha] 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-1[alpha] knockdown, suggesting a critical role of HIF-1[alpha] in the underlying mechanism of GATA3-mediated effects. Our findings suggest that GATA3 stabilizes HIF-1[alpha] to enhance cancer invasiveness under hypoxia and support the GATA3/HIF-1[alpha] axis as a potential therapeutic target for cancer treatment. Oncogene (2017) 36, 4243-4252; doi: 10.1038/onc.2017.8; published online 6 March 2017 |
| doi_str_mv | 10.1038/onc.2017.8 |
| format | Article |
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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-1[alpha] 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-1[alpha] under hypoxia to inhibit ubiquitination and proteasomal degradation of HIF-1[alpha], which is independent of HIF-1[alpha] prolyl hydroxylation. Chromatin immunoprecipitation assays show that the GATA3/HIF-1[alpha] 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-1[alpha] knockdown, suggesting a critical role of HIF-1[alpha] in the underlying mechanism of GATA3-mediated effects. Our findings suggest that GATA3 stabilizes HIF-1[alpha] to enhance cancer invasiveness under hypoxia and support the GATA3/HIF-1[alpha] axis as a potential therapeutic target for cancer treatment. Oncogene (2017) 36, 4243-4252; doi: 10.1038/onc.2017.8; published online 6 March 2017</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2017.8</identifier><language>eng</language><publisher>New York: Nature Publishing Group</publisher><subject>Analysis ; Anoxia ; Cancer ; Cancer cells ; Cell adhesion & migration ; Chromatin ; GATA-3 protein ; Head & neck cancer ; Hydroxylation ; Hypoxia ; Hypoxia-inducible factor 1 ; Hypoxia-inducible factor 1a ; Immunodeficiency ; Immunoprecipitation ; Invasiveness ; Melanoma ; Pathogenesis ; Proteasomes ; Proteins ; Rodents ; Squamous cell carcinoma ; Ubiquitination</subject><ispartof>Oncogene, 2017-07, Vol.36 (30), p.4243</ispartof><rights>COPYRIGHT 2017 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 27, 2017</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids></links><search><creatorcontrib>Lin, M-C</creatorcontrib><creatorcontrib>Lin, J-J</creatorcontrib><creatorcontrib>Hsu, C-L</creatorcontrib><creatorcontrib>Juan, H-F</creatorcontrib><creatorcontrib>Lou, P-J</creatorcontrib><creatorcontrib>Huang, M-C</creatorcontrib><title>GATA3 interacts with and stabilizes HIF-1[alpha] to enhance cancer cell invasiveness</title><title>Oncogene</title><description>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-1[alpha] 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-1[alpha] under hypoxia to inhibit ubiquitination and proteasomal degradation of HIF-1[alpha], which is independent of HIF-1[alpha] prolyl hydroxylation. Chromatin immunoprecipitation assays show that the GATA3/HIF-1[alpha] 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-1[alpha] knockdown, suggesting a critical role of HIF-1[alpha] in the underlying mechanism of GATA3-mediated effects. Our findings suggest that GATA3 stabilizes HIF-1[alpha] to enhance cancer invasiveness under hypoxia and support the GATA3/HIF-1[alpha] axis as a potential therapeutic target for cancer treatment. Oncogene (2017) 36, 4243-4252; doi: 10.1038/onc.2017.8; published online 6 March 2017</description><subject>Analysis</subject><subject>Anoxia</subject><subject>Cancer</subject><subject>Cancer cells</subject><subject>Cell adhesion & migration</subject><subject>Chromatin</subject><subject>GATA-3 protein</subject><subject>Head & neck cancer</subject><subject>Hydroxylation</subject><subject>Hypoxia</subject><subject>Hypoxia-inducible factor 1</subject><subject>Hypoxia-inducible factor 1a</subject><subject>Immunodeficiency</subject><subject>Immunoprecipitation</subject><subject>Invasiveness</subject><subject>Melanoma</subject><subject>Pathogenesis</subject><subject>Proteasomes</subject><subject>Proteins</subject><subject>Rodents</subject><subject>Squamous cell carcinoma</subject><subject>Ubiquitination</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptj01LAzEQhoMoWKsXf0HA86752qQ5LsV-QMHL3kSWNDtpU7bZutlW8NebYkEPMjADwzPvOy9Cj5TklPDJcxdszghV-eQKjahQMisKLa7RiOiCZJpxdovuYtwRQpQmbISqeVmVHPswQG_sEPGnH7bYhAbHwax9678g4sVyltE30x625h0PHYawNcECtufeYwttmxROJvoTBIjxHt0400Z4uMwxqmYv1XSRrV7ny2m5yjbnb4RWsBZGCyc1V1w6qx1IxQSz1FLOC9swZwiYteRKNExoDpIy4rQEZsyEj9HTj-yh7z6OEId61x37kBxrmqIqqpUkv9TGtFD74LohJd37aOtSaM1ZspaJyv-hUjWw97YL4Hza_zn4BuYVa4s</recordid><startdate>20170727</startdate><enddate>20170727</enddate><creator>Lin, M-C</creator><creator>Lin, J-J</creator><creator>Hsu, C-L</creator><creator>Juan, H-F</creator><creator>Lou, P-J</creator><creator>Huang, M-C</creator><general>Nature Publishing Group</general><scope>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope></search><sort><creationdate>20170727</creationdate><title>GATA3 interacts with and stabilizes HIF-1[alpha] to enhance cancer cell invasiveness</title><author>Lin, M-C ; 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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-1[alpha] 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-1[alpha] under hypoxia to inhibit ubiquitination and proteasomal degradation of HIF-1[alpha], which is independent of HIF-1[alpha] prolyl hydroxylation. Chromatin immunoprecipitation assays show that the GATA3/HIF-1[alpha] 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-1[alpha] knockdown, suggesting a critical role of HIF-1[alpha] in the underlying mechanism of GATA3-mediated effects. Our findings suggest that GATA3 stabilizes HIF-1[alpha] to enhance cancer invasiveness under hypoxia and support the GATA3/HIF-1[alpha] axis as a potential therapeutic target for cancer treatment. Oncogene (2017) 36, 4243-4252; doi: 10.1038/onc.2017.8; published online 6 March 2017</abstract><cop>New York</cop><pub>Nature Publishing Group</pub><doi>10.1038/onc.2017.8</doi></addata></record> |
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| subjects | Analysis Anoxia Cancer Cancer cells Cell adhesion & migration Chromatin GATA-3 protein Head & neck cancer Hydroxylation Hypoxia Hypoxia-inducible factor 1 Hypoxia-inducible factor 1a Immunodeficiency Immunoprecipitation Invasiveness Melanoma Pathogenesis Proteasomes Proteins Rodents Squamous cell carcinoma Ubiquitination |
| title | GATA3 interacts with and stabilizes HIF-1[alpha] to enhance cancer cell invasiveness |
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