Flightless-I mediates the repression of estrogen receptor alpha target gene expression by the glucocorticoid receptor in MCF-7 cells

Abstract

The human homologue of flightless-I (FLII) belong to the gelsolin protein family and contain a gelsolin-like domain at the C-terminus and a leucine-rich repeat (LRR) domain at the N-terminus. FLII regulates estrogen receptor alpha (ER alpha) and glucocorticoid receptor (GR)-mediated transcription by direct interaction through different domains, suggestive of its potential role in the crosstalk between the ER alpha and GR signaling pathway. Here, we demonstrate that FLII plays a critical role in GR-mediated repression of ER alpha target gene expression. In FLII-depleted cells, the reduction in 17-beta-estradiol (E2)- induced ER alpha occupancy following treatment with dexamethasone (Dex) at the estrogen responsive element (ERE) site of the ER alpha target gene was significantly inhibited. The ERE binding of GR by the cotreatment with E2 and Dex was significantly inhibited by FLII depletion, indicating that FLII is required for the recruitment of GR at the ERE sites of ER alpha target genes. In addition, the recruitment of ER alpha-induced FLII to ERE sites was significantly reduced by Dex treatment. In protein binding assays, GR inhibited the E2-induced interaction between ER alpha and FLII, suggesting that GR interferes with the binding of ER alpha and FLII at the ER alpha target genes, resulting in the release of ER alpha and FLII from EREs. Taken together, our data reveal an unknown mechanism by which the transcription coactivator FLII regulates the GR-mediated repression of ER alpha target gene expression in MCF-7 cells.