The corepressor Alien as a novel tumor suppressor?

Abstract

Alien has been characterized as a corepressor for nuclear hormone receptors that harbor a silencing domain such as the thyroid hormone receptor (TR), the vitamin D3 receptor (VDR) and DAX-1. In addition, the androgen receptor (AR), a steroid hormone receptor, interacts with Alien. Alien enhances gene silencing mediated by TR, VDR and DAX-1, whereas Alien inhibits AR-mediated transactivation. The inhibition of AR by Alien seems to be restricted to cases where AR is bound to AR antagonists. In line with this, Alien inhibits AR target gene expression and human prostate cancer cell proliferation in an antagonist-specific manner indicating that Alien has an inhibitory role for cell cycle progression. Alien mediates gene silencing by recruitment of histone deacetylase activity and interestingly through nucleo-some assembly activity. Hereby, Alien enhances nucleosome positioning mediated by nucleosome assembly protein 1, which suggests a novel molecular mechanism of corepressor function. Using a proteomic approach to identify Alien interacting partners, we detected the cell cycle factor E2F1 to bind to Alien in vivo. The E2F1-mediated transactivation and E2F target gene expression is inhibited by Alien, and in line with this Alien is observed to repress cell cycle progression.