Modulation of aryl hydrocarbon receptor activity by four and a half LIM domain 2

Abstract

The aryl hydrocarbon receptor (AhR) mediates transcriptional effects of a diverse array of ligands including environmental contaminants that have been linked to various cancers. The transcriptional activity of the AhR is modulated by different coregulators such as the p160 family members of coactivators and nuclear receptor coactivator 4 (NcoA4). In this study, we provide novel evidence that four and a half LIM only protein 2 (FHL2) interacts with and differentially modulates the transcriptional activity of AhR. Co-immunoprecipitation studies indicate that FHL2 interacts with AhR in a ligand-independent manner but not with its heterodimeric partner, AhR nuclear translocator (ARNT). Overexpression of FHL2 enhanced AhR-mediated expression of a luciferase reporter gene in a dose- and ligand-dependent manner in COS cells. Furthermore, FHL2 cooperated with NcoA4 to synergistically enhance AhR transcriptional activity in these cells. However, the impact of FHL2 on AhR transcriptional activity was cell-specific: FHL2 facilitated AhR action in MCF-7 and PC-3 cells, whereas it suppressed AhR activity in T47D and LNCaP cells. These results of reporter gene studies were corroborated by the impact of FHL2 overexpression on, an established target gene of AhR, cytochrome P450 (CYP1A1) expression. We also demonstrated a potential competition of AhR and androgen receptor (AR) for FHL2 availability in COS cells, as FHL2-facilitation was significantly decreased in the presence of liganded AR. These findings indicate a functional interaction between AhR and FHL2 that modulates the activity of AhR and therefore could affect its role in cancer progression or development.