Suppression of CHK1 by ETS family members promotes DNA damage response by-pass and tumorigenesis

摘要

The ETS family of transcription factors has been repeatedly implicated in tumorigenesis. In prostate cancer, ETS family members such as ERG, ETV1, ETV4 and ETV5 are frequently overexpressed due to chromosomal translocations, but the molecular mechanisms by which they promote prostate tumorigenesis remain largely undefined. Here we show that ETS family members such as ERG and ETV1 directly repress the expression of the checkpoint kinase 1 (CHK1), a key DNA Damage Response (DDR) cell cycle regulator essential for the maintenance of genome integrity. Critically, we find that ERG expression correlates with CHK1 downregulation in human patients, and demonstrate that Chk1 heterozygosity promotes the progression of high-grade prostatic intraepithelial neoplasia (HGPIN) into prostatic invasive carcinoma (CaP) in Pten^+/− mice. Importantly, CHK1 downregulation sensitizes prostate tumor cells to etoposide but not to docetaxel treatment. Thus, we identify CHK1 as a key functional target of the ETS proto-oncogenic family with important therapeutic implications.