{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T01:38:27Z","timestamp":1791250707161,"version":"4.1.0"},"reference-count":31,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2014,10,30]],"date-time":"2014-10-30T00:00:00Z","timestamp":1414627200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA026038-35"],"award-info":[{"award-number":["R01CA026038-35"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001352","name":"National University of Singapore","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001352","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2015,5]]},"abstract":"<jats:p>Bromodomain and extra terminal domain (BET) proteins are important epigenetic regulators facilitating the transcription of genes in chromatin areas linked to acetylated histones. JQ1, a BET protein inhibitor, has antiproliferative activity against many cancers, mainly through inhibition of c\u2010MYC and upregulation of p21. In this research, we investigated the use of JQ1 for human osteosarcoma (OS) treatment. JQ1 significantly inhibited the proliferation and survival of OS cells inducing G1 cell cycle arrest, premature senescence, but little effect on apoptosis. Interestingly, c\u2010MYC protein levels in JQ1\u2010treated cells remained unchanged, whereas the upregulation of p21 protein was still observable. Although effective <jats:italic>in vitro<\/jats:italic>, JQ1 alone failed to reduce the size of the MNNG\/HOS xenografts in immunocompromised mice. To overcome the resistance of OS cells to JQ1 treatment, we combined JQ1 with rapamycin, an mammalian target of rapamycin (mTOR) inhibitor. JQ1 and rapamycin synergistically inhibited the growth and survival of OS cells <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. We also identified that RUNX2 is a direct target of bromodomain\u2010containing protein 4 (BRD4) inhibition by JQ1 in OS cells. Chromatin immunoprecipitation (ChIP) showed that enrichment of BRD4 protein around RUNX2 transcription start sites diminished with JQ1 treatment in MNNG\/HOS cells. Overexpression of RUNX2 protected JQ1\u2010sensitive OS cells from the effect of JQ1, and siRNA\u2010mediated inhibition of RUNX2 sensitized the same cells to JQ1. In conclusion, our findings suggest that JQ1, in combination with rapamycin, is an effective chemotherapeutic option for OS treatment. We also show that inhibition of RUNX2 expression by JQ1 partly explains the antiproliferative activity of JQ1 in OS cells.<\/jats:p>","DOI":"10.1002\/ijc.29269","type":"journal-article","created":{"date-parts":[[2014,10,11]],"date-time":"2014-10-11T22:16:02Z","timestamp":1413065762000},"page":"2055-2064","source":"Crossref","is-referenced-by-count":95,"title":["Synergistic effect of <scp>JQ<\/scp>1 and rapamycin for treatment of human osteosarcoma"],"prefix":"10.1002","volume":"136","author":[{"given":"Dhong Hyun","family":"Lee","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology Cedars\u2010Sinai Medical Center, UCLA School of Medicine Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Qi","sequence":"additional","affiliation":[{"name":"Division of Hematologic Neoplasia Dana\u2010Farber Cancer Institute Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Bradner","sequence":"additional","affiliation":[{"name":"Division of Hematologic Neoplasia Dana\u2010Farber Cancer Institute Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan W.","family":"Said","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Santa Monica\u2010University of California\u2010Los Angeles Medical Center Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ngan B.","family":"Doan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Santa Monica\u2010University of California\u2010Los Angeles Medical Center Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Forscher","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology Cedars\u2010Sinai Medical Center, UCLA School of Medicine Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Yang","sequence":"additional","affiliation":[{"name":"National Cancer Institute and Cancer Science Institute National University of Singapore  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Phillip","family":"Koeffler","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology Cedars\u2010Sinai Medical Center, UCLA School of Medicine Los Angeles CA"},{"name":"National Cancer Institute and Cancer Science Institute National University of Singapore  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,10,30]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/138161213804581918"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1216363109"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01020-07"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09504"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10334"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.08.017"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-02-413021"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.003"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0418"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-2281"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/627254"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1212704"},{"key":"e_1_2_5_14_1","first-page":"3808","article-title":"c\u2010myc amplification and expression in newly established human osteosarcoma cell lines","volume":"47","author":"Bogenmann E","year":"1987","journal-title":"Cancer Res"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2011.03.001"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/oncsis.2013.10"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0065-2571(84)90007-4"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-1947"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-0367"},{"key":"e_1_2_5_20_1","first-page":"7","article-title":"Image Processing with ImageJ","volume":"11","author":"Abramoff MDM","year":"2004","journal-title":"Biophotonics Int"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkl024"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.180309597"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200809167"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1105136"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.03.036"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.03.035"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.22.7982-7992.2002"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/282745"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1209"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24218"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4511"}],"container-title":["International Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fijc.29269","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.29269","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T03:23:13Z","timestamp":1696389793000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ijc.29269"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,10,30]]},"references-count":31,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2015,5]]}},"alternative-id":["10.1002\/ijc.29269"],"URL":"https:\/\/doi.org\/10.1002\/ijc.29269","archive":["Portico"],"relation":{},"ISSN":["0020-7136","1097-0215"],"issn-type":[{"value":"0020-7136","type":"print"},{"value":"1097-0215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,10,30]]}}}