GATA2 and SMAD4 knock-down in prostate 1F5 cells quantified by RNA-seq

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.

包括拷贝数扩增在内的异常体细胞基因组改变，是癌症基因组的标志性特征。我们此前曾对前列腺癌（PCa）的基因组特征全景进行过分析，但尚未明确其中具备预后潜力的潜在致病基因。目前仍不清楚体细胞基因组事件与遗传性生殖系变异如何协同作用，进而推动癌症进展。本研究通过整合基因组学与实验分析，鉴定出GATA2是前列腺癌中一类常见的转移相关基因组扩增事件，并发现其可在转录水平上自主增强自身表达。功能实验结果显示，GATA2可与SMAD4发生物理相互作用并协同结合，实现全基因组范围内的染色质共占据，共同调控前列腺癌相关基因以及TGF-β（转化生长因子β）信号通路等转移相关通路的表达。从机制层面来看，GATA2与SMAD4协同作用，可增强TGF-β与AR（雄激素受体，Androgen Receptor）信号通路，并通过直接结合TGF-β1的远端增强子，激活TGF-β1的基因表达。值得注意的是，GATA2与SMAD4可全局性介导前列腺癌的遗传性患病风险，并与HOXB13在前列腺癌风险相关的rs339331/6q22增强子区域形成转录复合物，最终上调前列腺癌易感基因RFX6的表达水平。