{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T08:40:16Z","timestamp":1764146416635,"version":"3.46.0"},"reference-count":49,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":24,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Endometrial cancer (EC) is the most prevalent gynecological malignancy globally. Here, we explored the role of E74\u2010like ETS transcription factor 4 (ELF4) in EC progression. Using the TISIDB web tool to analyze TCGA data, we found that elevated ELF4 expression correlates with higher histological grades and reduced overall survival in EC patients. Tissue microarray analysis confirmed a grade\u2010dependent increase in ELF4 protein levels. Knockdown of ELF4 in EC cell lines (AN3CA, HEC\u20101A) and patient\u2010derived EC cells suppressed proliferation, cell cycle progression, and cancer stem cell (CSC) activity. Database analysis and RNA interference identified cyclin\u2010dependent kinase 6 (CDK6) as a downstream target of ELF4. ELF4 silencing reduced CDK6 mRNA and protein expression, while chromatin immunoprecipitation revealed direct binding of ELF4 to the CDK6 promoter. Conversely, ELF4 overexpression upregulated CDK6. Knockdown of CDK6 or treatment with the CDK4\/6 inhibitor Palbociclib diminished tumorsphere formation and expression of stemness markers (OCT4, NANOG, c\u2010MYC) in both conventional and patient\u2010derived EC cells. We previously reported that the tribbles pseudokinase 3 (TRIB3)\/ELF4 complex transactivates CTNNB1 expression; here, we show that TRIB3 knockdown also downregulates CDK6 at mRNA and protein levels, suggesting cooperative regulation of CDK6 by ELF4 and TRIB3. In EC specimens, ELF4, TRIB3, and CDK6 expression positively correlated, and Kaplan\u2010Meier analysis indicated that high co\u2010expression of these genes predicted the poorest overall survival. Collectively, our findings establish the ELF4\/TRIB3\/CDK6 axis as a critical regulator of EC progression and CSC maintenance, highlighting its potential as a therapeutic target for EC.<\/jats:p>","DOI":"10.1002\/jcp.70113","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T10:07:48Z","timestamp":1764065268000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ELF4\/TRIB3\/CDK6 Axis Promotes Cancer Stem Cell Activity in Endometrial Cancer"],"prefix":"10.1002","volume":"240","author":[{"given":"Chun\u2010Yu","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine Tungs' Taichung MetroHarbor Hospital  Taichung Taiwan"},{"name":"Post\u2010Baccalaureate Medicine, National Chung Hsing University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yueh\u2010Chun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Chung Shan Medical University Hospital  Taichung Taiwan"},{"name":"School of Medicine Chung Shan Medical University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu\u2010Hao","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Chung Shan Medical University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen\u2010Ling","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Chung Shan Medical University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2283-1377","authenticated-orcid":false,"given":"Wen\u2010Wei","family":"Chang","sequence":"additional","affiliation":[{"name":"Department 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