p53 gain-of-function mutation induces metastasis via Brd4-dependent Csf-1 expression.

TP53 mutations are frequent in esophageal squamous cell carcinoma (ESCC) and other SCCs, and are associated with a proclivity for metastasis. Here, we report that Colony-stimulating factor-1 (Csf-1) expression is upregulated significantly in a p53-R172H-dependent manner in metastatic lung lesions of ESCC. The p53-R172H-dependent 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. In Trp53R172H tumor cells, p53 occupies the Csf-1 promoter. The Csf-1 locus is enriched with histone 3 lysine 27 acetylation (H3K27ac), which likely is permissive for fostering an interaction between 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-dependent Brd4-Csf-1 axis that promotes ESCC lung metastasis, and suggest avenues for therapeutic strategies for this difficult-to-treat disease.