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Here, we show that the hyperactivation of RelB fosters prostate cancer (PCa) osteolytic metastasis by coordinating interleukin\u20108 (IL\u20108) and calcium\u2010binging protein A4 (S100A4).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The factors promoting PCa bone metastasis were investigated in sera from PCa patients and tumour tissues derived from nude mice using immunohistochemical analysis and enzyme\u2010linked immunosorbent assays (ELISA). Cell mobility and mineralization were quantified using BioStation CT and Osteolmage assay. The relative cistrome was investigated in advanced PCa cells by standard transcriptional analyses, including the luciferase reporter response, site\u2010directed mutagenesis, and chromatin immunoprecipitation (ChIP) assay. PCa cell\u2010initiated tumour formation, expansion, and bone metastasis were validated in mice using multiple approaches, including orthotopic, intraskeletal, and caudal arterial implantation models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>IL\u20108 and S100A4 correlated with patient Gleason scores and bone metastasis. RelB upregulated IL\u20108, facilitating androgen receptor (AR)\u2010independent growth. RelB\u2010Sp1 interaction enhanced epithelial\u2010mesenchymal transition (EMT) by activating Snail and Twist. RelB\u2010NFAT1c super\u2010enhancer upregulated S100A4 in the organization of the cytoskeleton and bone metastasis. The RelB\u2010IL\u20108\u2010S100A4 signalling axis was confirmed to promote osteolytic metastasis in nude mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>RelB\u2010IL\u20108 reciprocally promoted EMT by activating inflammatory signalling and inactivating AR signalling. IL\u20108 is essential for provoking PCa metastasis but insufficient to drive bone metastasis. IL\u20108\u2010S100A4 cooperation was necessary for metastatic cells to target the bone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>RelB activates inflammatory signalling by upregulating IL\u20108 and suppressing AR.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>RelB upregulates S100A4 by cooperating with NFATC1.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>IL\u20108 boosts EMT by activating Snail 1 and Twist 1, and S100A4 exacerbates osteolytic metastasis via calcium consumption.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>RelB harnesses IL\u20108 and S100A4 to drive PCa osteolytic metastasis.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70058","type":"journal-article","created":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T04:25:14Z","timestamp":1729139114000},"source":"Crossref","is-referenced-by-count":6,"title":["Insight 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