ChIP-seq data for studying GATA2 and SMAD4 in prostate 1F5 and LNCaP cells.

Aberrant somatic genomic alteration including copy number amplification is a hallmark of cancer genomes. We previously profiled genomic landscapes of prostate cancer (PCa), yet the underlying causal genes with prognostic potential has not been defined. It remains unclear how a somatic genomic event cooperates with inherited germline variants contribute to progression. In this study, by integrated genomics and experimental analysis, we identified GATA2 as a prevalent metastasis-associated genomic amplification and transcriptionally augmenting its own expression in PCa. Functional experiments demonstrated that GATA2 physically interacts and cooperates with SMAD4 for genome-wide chromatin co-occupancy and co-regulation of PCa genes and metastasis pathways like TGFß signaling. Mechanistically, GATA2 is cooperative with SMAD4 to enhance TGFß and AR signaling pathways and activates the expression of TGFß1 via directly binding to a distal enhancer of TGFß1. Strinkingly, GATA2 and SMAD4 globally mediated inherited PCa risk and formed a transcriptional complex with HOXB13 at the PCa risk-associated rs339331/6q22 enhancer, leading to increased expression of the PCa susceptibility gene RFX6.