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Here, we report that colony-stimulating factor-1 (CSF-1) expression is upregulated significantly in a p53-R172H\u2013dependent manner in metastatic lung lesions of ESCC. The p53-R172H\u2013dependent CSF-1 signaling, through its cognate receptor CSF-1R, increases tumor cell invasion and lung metastasis, which in turn is mediated in part through Stat3 phosphorylation and epithelial-to-mesenchymal transition (EMT). In Trp53R172H tumor cells, p53 occupies the Csf-1 promoter. The Csf-1 locus is enriched with histone 3 lysine 27 acetylation (H3K27ac), which is likely permissive for fostering an interaction between bromodomain-containing domain 4 (BRD4) and p53-R172H to regulate Csf-1 transcription. Inhibition of BRD4 not only reduces tumor invasion and lung metastasis but also reduces circulating CSF-1 levels. Overall, our results establish a novel p53-R172H\u2013dependent BRD4\u2013CSF-1 axis that promotes ESCC lung metastasis and suggest avenues for therapeutic strategies for this difficult-to-treat disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>The invasion\u2013metastasis cascade is a recalcitrant barrier to effective cancer therapy. We establish that the p53-R172H\u2013dependent BRD4-CSF-1 axis is a mediator of prometastatic properties, correlates with patient survival and tumor stages, and its inhibition significantly reduces tumor cell invasion and lung metastasis. This axis can be exploited for therapeutic advantage.<\/jats:p>\n                    <jats:p>This article is featured in Selected Articles from This Issue, p. 2489<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-23-0601","type":"journal-article","created":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T11:22:18Z","timestamp":1694085738000},"page":"2632-2651","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["p53 Gain-of-Function Mutation Induces Metastasis via BRD4-Dependent CSF-1 Expression"],"prefix":"10.1158","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1153-3326","authenticated-orcid":false,"given":"Gizem","family":"Efe","sequence":"first","affiliation":[{"name":"1Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York."},{"name":"2Department of Genetics and Development, Columbia University, New York, New 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