{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:16:51Z","timestamp":1788239811227,"version":"build-2803163510"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>\n                    ZEB1 is a key driver of breast cancer pathogenesis and therapy resistance, largely through its ability to promote cancer stem cells (CSCs). Although tumor-secreted cytokines such as IL-6 are known to support tumor progression, how their expression is regulated by upstream transcriptional factors such as ZEB1 remains incompletely understood. Here, we identify IL-6 as a direct transcriptional target of ZEB1 and reveal an epigenetic dimension associated with this regulation. Mechanistically, ZEB1 binds to specific E2-box elements within the IL-6 promoter and activates its transcription. The IL-6 promoter exhibits local DNA methylation, and ZEB1-dependent IL-6 expression was further enhanced by DNA methyltransferase and histone deacetylase inhibitors, suggesting that the local epigenetic context constrains IL-6 transcription. ZEB1 overexpression was also accompanied by enrichment of the active histone marks H3K27ac and H3K4me3 at the IL-6 promoter, consistent with a more transcriptionally permissive local chromatin state. Functionally, the ZEB1-induced IL-6 expression enhanced CSC-associated properties\n                    <jats:italic>in vitro<\/jats:italic>\n                    and tumor-initiating capacity\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Conversely, IL-6 knockdown attenuated ZEB1-induced CSC-associated phenotypes, whereas pharmacological IL-6 neutralization reduced xenograft burden and CSC-associated populations\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Collectively, our findings establish the ZEB1\u2013IL-6 axis as an important regulator of triple-negative breast cancer (TNBC) stemness and indicate that ZEB1-dependent IL-6 activation is influenced by the local epigenetic context. These findings support further investigation of the ZEB1\u2013IL-6 axis as a potential therapeutic target in ZEB1-high TNBC.\n                  <\/jats:p>","DOI":"10.3389\/fonc.2026.1929305","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T04:26:28Z","timestamp":1788236788000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ZEB1 directly activates IL-6 to promote triple-negative breast cancer stemness in an epigenetically constrained context"],"prefix":"10.3389","volume":"16","author":[{"given":"Weiyue","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Biological Science and Medical Engineering, Beihang University","place":["Beijing, China"]},{"name":"Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Ma","sequence":"additional","affiliation":[{"name":"Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2024.189168","article-title":"Dual perspective on autophagy in glioma: detangling the dichotomous mechanisms of signaling pathways for therapeutic insights","volume":"1879","author":"Kundu","year":"2024","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"B2","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.stem.2025.01.010","article-title":"PSPC1 exerts an oncogenic role in AML by regulating a leukemic transcription program in cooperation with PU.1","volume":"32","author":"Hong","year":"2025","journal-title":"Cell Stem Cell"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1631\/jzus.b1300264","article-title":"Harnessing the immune system for the treatment of breast cancer","volume":"15","author":"Jiang","year":"2014","journal-title":"J Zhejiang Univ Sci B"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jncc.2025.05.006","article-title":"Do ethnic disparities exist in disease burden and healthcare utilization of male breast cancer? 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