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<!DOCTYPE html> <html lang="ko"> <head> <title>OASIS Repository@POSTECHLIBRARY: Loss of DAB2IP in RCC cells enhances their growth and resistance to mTOR-targeted therapies</title> <meta http-equiv="Content-Type" content="text/html; charset=UTF-8" /> <meta name="Generator" content="DSpace 5.5" /> <meta name="viewport" content="width=device-width, initial-scale=1.0"> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="description" content="Postech OASIS Repository" /> <meta name="keywords" content="오아시스,레포지토리,리포지터리,저장소,포스텍,박태준학술정보관,포항공과대학교,포항공대,POSTECH,Pohang University of Science and Technology,도서관,IR,연구업적,학술실적,연구성과,dspace" /> <link rel="shortcut icon" href="/favicon.ico" type="image/x-icon"/> <link rel="search" type="application/opensearchdescription+xml" href="/open-search/description.xml" title="DSpace" /> <link rel="schema.DCTERMS" href="http://purl.org/dc/terms/" /> <link rel="schema.DC" href="http://purl.org/dc/elements/1.1/" /> <link rel="schema.OAK" href="http://www.oak.go.kr/terms/" /> <meta name="OAK.author" content="YUN, EUN JIN" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Zhou, Jiancheng" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Luo, Junhang" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Wu, Kaijie" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Kapur, Payal" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Pong, Rey-Chen" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Du, Yuefeng" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Wang, Bin" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Authement, C" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Hernandez, Elizabeth" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Yang, Jichen" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Xiao, Guanghua" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Cha Tai-Lung" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Wu, His-Chin" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Wu, Dapeng" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Margulis, Vitaly" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Lotan, Yair" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Brugarolas, Jame" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="He, Dalin" scheme="OAK.AUTHOR" /> <meta name="OAK.author" content="Hsieh, Jer-Tsong" scheme="OAK.AUTHOR" /> <meta name="DCTERMS.dateAccepted" content="2018-01-04T11:11:56Z" scheme="DCTERMS.W3CDTF" /> <meta name="DCTERMS.available" content="2018-01-04T11:11:56Z" scheme="DCTERMS.W3CDTF" /> <meta name="DCTERMS.created" content="2017-11-13" scheme="DCTERMS.W3CDTF" /> <meta name="DCTERMS.issued" content="2016-09-01" scheme="DCTERMS.W3CDTF" /> <meta name="OAK.identifier.issn" content="0950-9232" scheme="OAK.ISSN" /> <meta name="DC.identifier" content="https://oasis.postech.ac.kr/handle/2014.oak/39238" scheme="DCTERMS.URI" /> <meta name="DCTERMS.abstract" content="Targeted therapies using small-molecule inhibitors (SMIs) are commonly used in metastatic renal cell cancer (mRCC) patients; patients often develop drug resistance and eventually succumb to disease. Currently, understanding of mechanisms leading to SMIs resistance and any identifiable predictive marker(s) are still lacking. We discovered that DAB2IP, a novel Ras-GTPase-activating protein, was frequently epigenetically silenced in RCC, and DAB2IP loss was correlated with the overall survival of RCC patients. Loss of DAB2IP in RCC cells enhances their sensitivities to growth factor stimulation and resistances to SMI (such as mammalian target of rapamycin (mTOR) inhibitors). Mechanistically, loss of DAB2IP results in the activation of extracellular signal-regulated kinase/RSK1 and phosphoinositide-3 kinase/mTOR pathway, which synergizes the induction of hypoxia-inducible factor (HIF)-2 alpha expression. Consequently, elevated HIF-2 alpha suppresses p21/WAF1 expression that is associated with resistance to mTOR inhibitors. Thus combinatorial targeting both pathways resulted in a synergistic tumor inhibition. DAB2IP appears to be a new prognostic/predictive marker for mRCC patients, and its function provides a new insight into the molecular mechanisms of drug resistance to mTOR inhibitors, which also can be used to develop new strategies to overcome drug-resistant mRCC." /> <meta name="DC.language" content="English" /> <meta name="DC.publisher" content="NATURE PUBLISHING GROUP" /> <meta name="DC.relation" content="ONCOGENE" /> <meta name="DC.subject" content="ABERRANT PROMOTER METHYLATION" /> <meta name="DC.subject" content="PROTEIN HDAB2IP GENE" /> <meta name="DC.subject" content="PROSTATE-CANCER" /> <meta name="DC.subject" content="BREAST-CANCER" /> <meta name="DC.subject" content="TUMOR-SUPPRESSOR" /> <meta name="DC.subject" content="HEPATOCELLULAR-CARCINOMA" /> <meta name="DC.subject" content="RENAL-CARCINOMA" /> <meta name="DC.subject" content="DOWN-REGULATION" /> <meta name="DC.subject" content="ACTIVATION" /> <meta name="DC.subject" content="EXPRESSION" /> <meta name="DC.title" content="Loss of DAB2IP in RCC cells enhances their growth and resistance to mTOR-targeted therapies" /> <meta name="DC.type" content="Article" /> <meta name="DC.identifier" content="10.1038/onc.2016.4" /> <meta name="DC.identifier" content="28950" /> <meta name="DC.type" content="ART" /> <meta name="DC.identifier" content="ONCOGENE, v.35, no.35, pp.4663 - 4674" /> <meta name="DC.identifier" content="000382336300012" /> <meta name="DC.date" content="2019-02-01" scheme="DCTERMS.W3CDTF" /> <meta name="OAK.relation.page" content="4674" scheme="OAK.PAGE" /> <meta name="OAK.relation.issue" content="35" scheme="OAK.ISSUE" /> <meta name="OAK.relation.page" content="4663" scheme="OAK.PAGE" /> <meta name="OAK.relation.journal" content="ONCOGENE" scheme="OAK.JOURNAL" /> <meta name="OAK.relation.volume" content="35" scheme="OAK.VOLUME" /> <meta name="DC.contributor" content="YUN, EUN JIN" /> <meta name="DC.identifier" content="2-s2.0-84958092642" /> <meta name="DC.description" content="1" /> <meta name="DC.description" content="1" /> <meta name="DC.description" content="10" /> <meta name="DC.type" content="Article" /> <meta name="DC.subject" content="ABERRANT PROMOTER METHYLATION" /> <meta name="DC.subject" content="PROTEIN HDAB2IP GENE" /> <meta name="DC.subject" content="PROSTATE-CANCER" /> <meta name="DC.subject" content="BREAST-CANCER" /> <meta name="DC.subject" content="TUMOR-SUPPRESSOR" /> <meta name="DC.subject" content="HEPATOCELLULAR-CARCINOMA" /> <meta name="DC.subject" content="RENAL-CARCINOMA" /> <meta name="DC.subject" content="DOWN-REGULATION" /> <meta name="DC.subject" content="ACTIVATION" /> <meta name="DC.subject" content="EXPRESSION" /> <meta name="DC.relation" content="Biochemistry & Molecular Biology" /> <meta name="DC.relation" content="Oncology" /> <meta name="DC.relation" content="Cell Biology" /> <meta name="DC.relation" content="Genetics & Heredity" /> <meta name="DC.description" content="scie" /> <meta name="DC.description" content="scopus" /> <meta name="DC.relation" content="Biochemistry & Molecular Biology" /> <meta name="DC.relation" content="Oncology" /> <meta name="DC.relation" content="Cell Biology" /> <meta name="DC.relation" content="Genetics & Heredity" /> <meta name="citation_keywords" content="ABERRANT PROMOTER METHYLATION; PROTEIN HDAB2IP GENE; PROSTATE-CANCER; BREAST-CANCER; TUMOR-SUPPRESSOR; HEPATOCELLULAR-CARCINOMA; RENAL-CARCINOMA; DOWN-REGULATION; ACTIVATION; EXPRESSION; Article" /> <meta name="citation_title" content="Loss of DAB2IP in RCC cells enhances their growth and resistance to mTOR-targeted therapies" /> <meta name="citation_issn" content="0950-9232" /> <meta name="citation_publisher" content="NATURE PUBLISHING GROUP" /> <meta name="citation_author" content="YUN, EUN JIN" /> <meta name="citation_author" content="Zhou, Jiancheng" /> <meta name="citation_author" content="Luo, Junhang" /> <meta name="citation_author" content="Wu, Kaijie" /> <meta name="citation_author" content="Kapur, Payal" /> <meta name="citation_author" content="Pong, Rey-Chen" /> <meta name="citation_author" content="Du, Yuefeng" /> <meta name="citation_author" content="Wang, Bin" /> <meta name="citation_author" content="Authement, C" /> <meta name="citation_author" content="Hernandez, Elizabeth" /> <meta name="citation_author" content="Yang, Jichen" /> <meta name="citation_author" content="Xiao, Guanghua" /> <meta name="citation_author" content="Cha Tai-Lung" /> <meta name="citation_author" content="Wu, His-Chin" /> <meta name="citation_author" content="Wu, Dapeng" /> <meta name="citation_author" content="Margulis, Vitaly" /> <meta name="citation_author" content="Lotan, Yair" /> <meta name="citation_author" content="Brugarolas, Jame" /> <meta name="citation_author" content="He, Dalin" /> <meta name="citation_author" content="Hsieh, Jer-Tsong" /> <meta name="citation_date" content="2016-09-01" /> <meta name="citation_abstract_html_url" content="https://oasis.postech.ac.kr/handle/2014.oak/39238" /> <link rel="stylesheet" href="/css/bootstrap.min.css" defer /> <link rel="stylesheet" href="/css/layout.css" async /> <link rel="stylesheet" href="/css/mquery.css" defer /> <link rel="stylesheet" href="/css/slidebars.css" defer />  <link rel="stylesheet" href="/css/owl.carousel.css" defer />  <link rel="stylesheet" href="/css/owl.theme.css" defer /> <link rel="stylesheet" href="/css/bootstrap-partof.css" defer /> <script src="/js/jquery-1.9.1.min.js"></script> <script src="/js/jquery-ui.js"></script> <script src="/js/bootstrap.min.js"></script> <script src="/js/owl.carousel.min.js"></script> <script src="/js/common.js" defer></script> <script src="/utils.js" defer></script> <script src="/static/js/holder.js" defer></script> <script src="/static/js/choice-support.js" defer></script> <script src="/js/ms-clarity.js"></script> <script async src="https://www.googletagmanager.com/gtag/js?id=G-B9EHYYGM78"></script> <script> window.dataLayer = window.dataLayer || []; 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Journal Papers</strong></a> </div></div> </div> <div class="col_width sub_container add_widget"> <div class="sub_contents"> <script src="https://apis.google.com/js/platform.js" async defer></script> <script type="text/javascript"> // google plus api window.___gcfg = {lang: 'ko'}; (function() { var po = document.createElement('script'); po.type = 'text/javascript'; po.async = true; po.src = 'https://apis.google.com/js/platform.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(po, s); })(); </script> <div class="sub_title"> <h3> </h3> <div class="type_icon"> <span class="article_type">Article</span> </div> </div> <div class="view_top_box"> <div class="view_bt_box"> <span class="cited_span science_span">Cited <em>30</em> time in <img src="/image/common/webofscience.png" alt="webofscience"></span> <span class="cited_span">Cited <em>32</em> time in <img src="/image/common/scopus.png" alt="scopus"></span> </div> <div class="view_bt_area"> <span>Metadata Downloads</span> <form action="/export" method="post"> <input type="hidden" name="item_id" value="38900"/> <div class="view_downbt"> <ul> <li> <input type="submit" name="submit_export_dc" value="DC(XML)"/> </li> <li> <input type="submit" name="submit_export_excel" value="EXCEL"/> </li> </ul> </div> </form> </div> </div> <div class="view_contents"> <p class="view_title">Loss of DAB2IP in RCC cells enhances their growth and resistance to mTOR-targeted therapies <em class="a_l_ink a_l_scie">SCIE</em> <em class="a_l_ink a_l_scopus">SCOPUS</em> </p> <div class="view_inner_con"> <dl><dt>Title</dt><dd>Loss of DAB2IP in RCC cells enhances their growth and resistance to mTOR-targeted therapies</dd></dl> <dl><dt>Authors</dt><dd><a class="author"href="/browse?type=author&value=YUN%2C+EUN+JIN">YUN, EUN JIN</a>; <a class="author"href="/browse?type=author&value=Zhou%2C+Jiancheng">Zhou, Jiancheng</a>; <a class="author"href="/browse?type=author&value=Luo%2C+Junhang">Luo, Junhang</a>; <a class="author"href="/browse?type=author&value=Wu%2C+Kaijie">Wu, Kaijie</a>; <a class="author"href="/browse?type=author&value=Kapur%2C+Payal">Kapur, Payal</a>; <a class="author"href="/browse?type=author&value=Pong%2C+Rey-Chen">Pong, Rey-Chen</a>; <a class="author"href="/browse?type=author&value=Du%2C+Yuefeng">Du, Yuefeng</a>; <a class="author"href="/browse?type=author&value=Wang%2C+Bin">Wang, Bin</a>; <a class="author"href="/browse?type=author&value=Authement%2C+C">Authement, C</a>; <a class="author"href="/browse?type=author&value=Hernandez%2C+Elizabeth">Hernandez, Elizabeth</a>; <a class="author"href="/browse?type=author&value=Yang%2C+Jichen">Yang, Jichen</a>; <a class="author"href="/browse?type=author&value=Xiao%2C+Guanghua">Xiao, Guanghua</a>; <a class="author"href="/browse?type=author&value=Cha+Tai-Lung">Cha Tai-Lung</a>; <a class="author"href="/browse?type=author&value=Wu%2C+His-Chin">Wu, His-Chin</a>; <a class="author"href="/browse?type=author&value=Wu%2C+Dapeng">Wu, Dapeng</a>; <a class="author"href="/browse?type=author&value=Margulis%2C+Vitaly">Margulis, Vitaly</a>; <a class="author"href="/browse?type=author&value=Lotan%2C+Yair">Lotan, Yair</a>; <a class="author"href="/browse?type=author&value=Brugarolas%2C+Jame">Brugarolas, Jame</a>; <a class="author"href="/browse?type=author&value=He%2C+Dalin">He, Dalin</a>; <a class="author"href="/browse?type=author&value=Hsieh%2C+Jer-Tsong">Hsieh, Jer-Tsong</a></dd></dl> <dl><dt>Date Issued</dt><dd>2016-09-01 </dd></dl> <dl><dt>Publisher</dt><dd>NATURE PUBLISHING GROUP</dd></dl> <dl><dt>Abstract</dt><dd>Targeted therapies using small-molecule inhibitors (SMIs) are commonly used in metastatic renal cell cancer (mRCC) patients; patients often develop drug resistance and eventually succumb to disease. Currently, understanding of mechanisms leading to SMIs resistance and any identifiable predictive marker(s) are still lacking. We discovered that DAB2IP, a novel Ras-GTPase-activating protein, was frequently epigenetically silenced in RCC, and DAB2IP loss was correlated with the overall survival of RCC patients. Loss of DAB2IP in RCC cells enhances their sensitivities to growth factor stimulation and resistances to SMI (such as mammalian target of rapamycin (mTOR) inhibitors). Mechanistically, loss of DAB2IP results in the activation of extracellular signal-regulated kinase/RSK1 and phosphoinositide-3 kinase/mTOR pathway, which synergizes the induction of hypoxia-inducible factor (HIF)-2 alpha expression. Consequently, elevated HIF-2 alpha suppresses p21/WAF1 expression that is associated with resistance to mTOR inhibitors. Thus combinatorial targeting both pathways resulted in a synergistic tumor inhibition. DAB2IP appears to be a new prognostic/predictive marker for mRCC patients, and its function provides a new insight into the molecular mechanisms of drug resistance to mTOR inhibitors, which also can be used to develop new strategies to overcome drug-resistant mRCC.</dd></dl> <dl><dt>Keywords</dt><dd>ABERRANT PROMOTER METHYLATION; PROTEIN HDAB2IP GENE; PROSTATE-CANCER; BREAST-CANCER; TUMOR-SUPPRESSOR; HEPATOCELLULAR-CARCINOMA; RENAL-CARCINOMA; DOWN-REGULATION; ACTIVATION; EXPRESSION</dd></dl> <dl><dt>URI</dt><dd><a href="https://oasis.postech.ac.kr/handle/2014.oak/39238" class="link_type">https://oasis.postech.ac.kr/handle/2014.oak/39238</a></dd></dl> <dl><dt>DOI</dt><dd><a href="http://dx.doi.org/10.1038/onc.2016.4">10.1038/onc.2016.4</a></dd></dl> <dl><dt>ISSN</dt><dd>0950-9232</dd></dl> <dl><dt>Article Type</dt><dd>Article</dd></dl> <dl><dt>Citation</dt><dd>ONCOGENE, vol. 35, no. 35, page. 4663 - 4674, 2016-09-01</dd></dl> <dl class="file_item_dl"><dt>Files in This Item:</dt> <dd class="file_download">There are no files associated with this item.</dd> </dl> </div> <div class="record_bt_box"> <a href="/handle/2014.oak/39238?mode=full">Show full item record</a> </div> <div class="al_right"> </div> <div class="sns_wrap"> <div class="sns_box"> <p class="qr_box"><img src="https://api.qrserver.com/v1/create-qr-code/?size=66x66&data=https://oasis.postech.ac.kr/handle/2014.oak/39238" alt="qr_code"></p> <div class="sns_inner"> <ul> <li> <p><a href="http://www.mendeley.com/import/?url=https://oasis.postech.ac.kr/handle/2014.oak/39238" target="_blank"><img src="/image/common/mendeley_icon.gif" alt="mendeley" /></a></p> <p class="twitter_box"> <a href="https://twitter.com/share" class="tweet_bt twitter-share-button" data-lang="en" data-size="large" data-dnt="true">트윗하기</a> <script> !function(d, s, id) { var js, fjs = d.getElementsByTagName(s)[0]; if (!d.getElementById(id)) { js = d.createElement(s); js.id = id; js.src = "//platform.twitter.com/widgets.js"; fjs.parentNode.insertBefore(js, fjs); } }(document, "script", "twitter-wjs"); </script> </p> </li> <li class="facebook_li"> <span id="fb-root"></span> <script> (function(d, s, id) { var js, fjs = d.getElementsByTagName(s)[0]; if (d.getElementById(id)) return; js = d.createElement(s); js.id = id; js.src = "//connect.facebook.net/ko_KR/all.js#xfbml=1"; fjs.parentNode.insertBefore(js, fjs); }(document, 'script', 'facebook-jssdk')); </script> <span class="fb-like" data-send="true" data-layout="standard" data-width="450" data-show-faces="false" data-font="verdana"></span> </li> </ul> </div> </div> <p class="sns_text"> <span> Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.</span> </p> </div> </div> </div>  <div class="sub_right_box"> <div class="w_cc"> <h4 class="widget_title">Communities & Collection</h4> <ul> <li><a href="/handle/2014.oak/9215" class="cc_item">ETC</a> <ul> <li><a href="/handle/2014.oak/30060">1. 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