Identification and Function of Ets Target Genes Involved in Lung Cancer Progression.

摘要

Ets proteins regulate expression of genes involved in tumorigenesis. In lung cancer, increased Ets1 expression is associated with poor prognosis. We hypothesized that Ets1 contributes to lung tumorigenesis by binding to specific promoters that control transcription of genes involved in EMT, such as Twist1. We used a mouse lung cancer model with metastasis driven by conditionally activated Kras and concurrent tumor suppressor Lkb1 loss (KrasG12D/Lkb1L/L model) and a similar model but one that does not metastasize, driven by conditionally activated Kras alone (KrasG12D model). We measured expression of Twist in KrasG12D /Lkb1L/L and KrasG12D cell lines. Using ChIP assays, we determined whether Ets1 binds Twist1. We determined whether silencing Ets1 decreases Twist1 expression. Ets1 and Twist1 differ in gene expression between KrasG12D (low Ets1 and Twist1) and KrasG12D/Lkb1L/L (high Ets1 and Twist1) tumors. In human lung tumors, Twist1 and Ets1 staining positively correlate. ChIP assays confirm binding of Ets1 to the Twist1 promoter. Silencing Ets1 decreases Twist1 expression and decreases migration and invasion. Using both mouse and human lung cancer cell lines, we show that Ets1 regulates the expression of Twist1. Therapeutic targeting of EMT regulators could be useful to impair tumor metastasis.