{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T07:41:53Z","timestamp":1791531713992,"version":"4.3.4"},"reference-count":49,"publisher":"Wiley","issue":"47","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100017691","name":"Guangxi Key Research and Development Program","doi-asserted-by":"publisher","award":["GuiKe\u2010AB25069017"],"award-info":[{"award-number":["GuiKe\u2010AB25069017"]}],"id":[{"id":"10.13039\/501100017691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,8]]},"abstract":"ABSTRACT<\/jats:title>\n \n Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three\u2010dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi\u2010omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300\u2010mediated enhancer\u2010promoter looping at the\n SOX2<\/jats:italic>\n locus. Mechanistically, SMAD4 does not directly bind\n SOX2<\/jats:italic>\n regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant\n SOX2<\/jats:italic>\n activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non\u2010canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.\n <\/jats:p>","DOI":"10.1002\/advs.75839","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T14:28:07Z","timestamp":1779805687000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Non\u2010Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development"],"prefix":"10.1002","volume":"13","author":[{"given":"Qian","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University\u2010University of Edinburgh Institute (ZJU\u2010UoE Institute), Zhejiang University School of Medicine Zhejiang University Haining China"},{"name":"Edinburgh Medical School: 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