ETS1 regulates transcription in a / metastatic lung tumor model of non-small cell lung cancer

Distinct members of the Ets family of transcription factors act as positive or negative regulators of genes involved in cellular proliferation, development, and tumorigenesis. In human lung cancer, increased ETS1 expression is associated with poor prognosis and metastasis. We tested whether ETS1 contributes to lung tumorigenesis by binding to Twist1, a gene involved in tumor cell motility and dissemination. We used a mouse lung cancer model with metastasis driven by conditionally activated and concurrent tumor suppressor loss (/ model) and a similar model of lung cancer that does not metastasize, driven by conditionally activated alone ( model). We show that and gene expression differs between tumors (low and expression) and / tumors (high and expression). In human lung tumors, ETS1 and TWIST1 expression positively correlates and low combined ETS1 and TWIST1 levels are associated with improved survival compared to high levels. Using mouse cell lines derived from and / mouse models and the human lung cancer (A549) cell line, we show that ETS1 regulates expression. Chromatin immunoprecipitation assays confirm binding of ETS1 to the promoter. Overexpression studies show that ETS1 transactivates promoter activity in mouse and human cells. Silencing endogenous by siRNA in mouse cell lines decreases mRNA levels, decreases invasion, and increases cell growth. Ets1 and Twist1 are at the crossroad of several signaling pathways in cancer. Understanding their regulation may inform the development of therapies to impair lung tumor metastasis.