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Here we report distinct three-dimensional chromatin architectures between NEPC and CRPC tumors, which were recapitulated by isogenic cell lines undergoing NE transformation (NET). Mechanistically, pioneer factors such as FOXA2 initiate binding at NE enhancers to mediate regional DNA demethylation and induce neural transcription factor (TF) <jats:italic>NKX2-1<\/jats:italic> expression. NKX2-1 preferentially binds gene promoters and interacts with enhancer-bound FOXA2 through chromatin looping. NKX2-1 is highly expressed in NEPC and indispensable for NET of prostate cancer. NKX2-1\/FOXA2 further recruits p300\/CBP to activate NE enhancers, and pharmacological inhibition of p300\/CBP effectively blunts NE gene expression and abolishes NEPC tumor growth. Taken together, our study reports a hierarchical network of TFs governed by NKX2-1 in critically regulating chromatin remodeling and driving luminal-to-NE transformation and suggests promising therapeutic approaches to mitigate NEPC.<\/jats:p>","DOI":"10.1038\/s41588-025-02265-4","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T09:19:00Z","timestamp":1753089540000},"page":"1966-1980","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["NKX2-1 drives neuroendocrine transdifferentiation of prostate cancer via epigenetic and 3D chromatin remodeling"],"prefix":"10.1038","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4731-0762","authenticated-orcid":false,"given":"Xiaodong","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viriya","family":"Keo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4977-1310","authenticated-orcid":false,"given":"Irina","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanqing","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3404-7961","authenticated-orcid":false,"given":"Galina","family":"Gritsina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0883-8660","authenticated-orcid":false,"given":"Cheng-Kai","family":"Shiau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueying","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiushi","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6137-6659","authenticated-orcid":false,"given":"Peng","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin G.","family":"Sanda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor G.","family":"Corces","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Altemose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1137-4564","authenticated-orcid":false,"given":"Ruli","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3163-380X","authenticated-orcid":false,"given":"Jonathan C.","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2326-0409","authenticated-orcid":false,"given":"Jindan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"2265_CR1","doi-asserted-by":"publisher","first-page":"11428","DOI":"10.1073\/pnas.1902651116","volume":"116","author":"W Abida","year":"2019","unstructured":"Abida, W. et al. 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