ETS1 regulates Twist1 transcription in a Kras G12D / Lkb1 −/− metastatic lung tumor model of non-small cell lung cancer

AbstractDistinct 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 activatedKras and concurrent tumor suppressorLkb1 loss (KrasG12D/Lkb1−/− model) and a similar model of lung cancer that does not metastasize, driven by conditionally activatedKras alone (KrasG12D model). We show thatEts1 andTwist1 gene expression differs betweenKrasG12D tumors (lowEts1 andTwist1 expression) andKrasG12D/Lkb1−/− tumors (highEts1 andTwist1 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 fromKrasG12D andKrasG12D/Lkb1−/− mouse models and the human lung cancer (A549) cell line, we show that ETS1 regulatesTwist1 expression. Chromatin immunoprecipitation assays confirm binding of ETS1 to theTwist1 promoter. Overexpression studies show that ETS1 transactivatesTwist1 promoter activity in mouse and human cells. Silencing endogenousEts1 by siRNA in mouse cell lines decreasesTwist1 mRNA levels, decreases invas...
Source: Clinical and Experimental Metastasis - Category: Cancer & Oncology Source Type: research