{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:11:24Z","timestamp":1781842284171,"version":"3.54.5"},"reference-count":72,"publisher":"American Society for Clinical Investigation","issue":"10","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":52,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["P50CA196516"],"award-info":[{"award-number":["P50CA196516"]}]},{"name":"NIH","award":["P50CA196516"],"award-info":[{"award-number":["P50CA196516"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,15]]},"abstract":"<jats:p>\n                    Resistance to HIF-2\u03b1 inhibitors such as belzutifan underscores the need to better understand how HIF-2\u03b1 is transcriptionally regulated in clear cell renal cell carcinoma (ccRCC). Here, we uncover a cytokine-driven enhancer mechanism that sustains HIF-2\u03b1 expression through the JAK1\/STAT3 signaling pathway. Using a genome-wide CRISPR screen in von Hippel\u2013Lindau\u2013deficient (VHL-deficient) ccRCC cells, we identified SOCS3 as a key negative regulator of HIF-2\u03b1. Mechanistically, loss of SOCS3 activates JAK1\/STAT3 signaling, leading to the recruitment of STAT3 to distal enhancers upstream of endothelial PAS domain-containing protein (\n                    <jats:italic>EPAS1<\/jats:italic>\n                    ) that physically loop to its promoter to drive HIF-2\u03b1 transcription. This cytokine-enhancer circuit was recapitulated in samples from patients with ccRCC and functionally validated using CRISPR interference (CRISPRi), which disrupted enhancer-promoter looping and reduced tumor growth in HIF-2\u03b1\u2013dependent models. SOCS3 overexpression or pharmacologic inhibition of JAK1\/STAT3 markedly suppressed HIF-2\u03b1 expression and tumor progression both in vitro and in vivo. Unlike prior studies focusing on VHL\/HIF occupancy\u2013driven enhancer activation, this work defines a\n                    <jats:italic>trans<\/jats:italic>\n                    -acting cytokine\u2013JAK1\/STAT3 pathway that transcriptionally controls\n                    <jats:italic>EPAS1<\/jats:italic>\n                    . Together, these findings reveal a targetable enhancer mechanism that sustains HIF-2\u03b1 expression and suggest that combined inhibition of JAK1\/STAT3 and HIF-2\u03b1 may overcome therapeutic resistance in kidney cancer.\n                  <\/jats:p>\n                  <jats:p>We discovered that cytokine signaling drives kidney cancer by activating a genetic circuit that boosts HIF-2\u03b1 expression, offering new targets to overcome treatment resistance.<\/jats:p>","DOI":"10.1172\/jci201639","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T16:00:27Z","timestamp":1774368027000},"source":"Crossref","is-referenced-by-count":1,"title":["Genome-wide CRISPR screen identifies a cytokine-enhancer circuit driving HIF-2\u03b1 activation in renal cancer"],"prefix":"10.1172","volume":"136","author":[{"given":"Jun","family":"Fang","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy M.","family":"Simon","sequence":"additional","affiliation":[{"name":"Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."},{"name":"Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4746-4614","authenticated-orcid":true,"given":"Yunpeng","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianju","family":"Bi","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianxin","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Urology, Institute of Urologic Science and Technology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9073-3835","authenticated-orcid":true,"given":"Chengheng","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yayoi","family":"Adachi","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0248-1632","authenticated-orcid":true,"given":"James A.","family":"Nathan","sequence":"additional","affiliation":[{"name":"Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Department of Medicine, University of Cambridge, Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3552-7905","authenticated-orcid":true,"given":"Ram","family":"Mani","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Brugarolas","sequence":"additional","affiliation":[{"name":"Kidney Cancer Program, Simmons Comprehensive Cancer Center,"},{"name":"Department of Internal Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA."},{"name":"Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21871"},{"issue":"101","key":"B2","first-page":"341","article-title":"Immune checkpoint blockade as a novel immunotherapeutic strategy for renal cell carcinoma: a review of clinical trials","volume":"18","author":"Godwin","year":"2014","journal-title":"Discov Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(02)00044-2"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3844"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nrc885"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-1354"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nature12222"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0000083"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(02)00043-0"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2020.38.15_suppl.5003"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2103425"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-1054"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2020.38.15_suppl.TPS5094"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nature19796"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-1459"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/nature19795"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(03)00187-9"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208003"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.08.002"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/ni931"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3109\/08977194.2012.687375"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.18632\/oncoscience.272"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3858\/emm.2008.40.5.479"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00887-y"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.10.025"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3437"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102726"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/srep18928"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.08.025"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/436981"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2013.10.029"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/srep07465"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nrm4010"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku095"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2013.08.031"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2013.10.008"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200607020"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2501"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/nature05029"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.333"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-11-0098"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110055"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208719"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1021\/ml100146z"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1126\/science.8197455"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1126\/science.1071545"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-020-00228-x"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-0375"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.12.004"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb1222"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3109\/10409238.2013.838205"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2015.05.007"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-06008-3"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13010042"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-020-00490-x"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2370"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.168864"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.3390\/cells7080102"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2015.02.013"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-021-00926-5"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1470368"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00566-3"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.11.022"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1126\/science.adf1329"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1126\/science.ade8520"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13184588"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1126\/science.aap8411"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1923"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2008-9-9-r137"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw257"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-323"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/201639\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T15:49:52Z","timestamp":1779205792000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/201639"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,24]]},"references-count":72,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,3,24]]},"published-print":{"date-parts":[[2026,5,15]]}},"alternative-id":["10.1172\/JCI201639"],"URL":"https:\/\/doi.org\/10.1172\/jci201639","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,24]]},"article-number":"e201639"}}