ETS variant 1 regulates matrix metalloproteinase-7 transcription in LNCaP prostate cancer cells

Abstract

Prostate cancer is characterized by the recurrent translocation of ETS transcription factors, including ETS variant 1 (ETV1) [also known as ETS-related 81 (ER81)]. Transgenic ETV1 mice develop prostatic intraepithelial neoplasia, yet the mechanisms by which ETV1 exerts its deleterious function remain largely unexplored. In this study, we demonstrated that ETV1 is capable of binding to the matrix metalloproteinase-7 (MMP-7) gene promoter both in vitro and in vivo. ETV1 stimulated the activity of the MMP-7 promoter, which was suppressed upon mutation of two ETV1 binding sites located within 200 base pairs upstream of the MMP-7 transcription start site. ETV1 overexpression in human LNCaP prostate cancer cells induced endogenous MMP-7 gene transcription, whereas ETV1 downregulation had the opposite effect. While MMP-7 overexpression did not influence LNCaP cell proliferation, it increased cell migration, which may be important during later stages of tumorigenesis. Finally, MMP-7 mRNA was significantly overexpressed in human prostate tumors compared to normal tissue. Together, these results showed that MMP-7 is a bona fide ETV1 target gene, implicating that MMP-7 upregulation is partially responsible for the oncogenic effects of ETV1 in the prostate.