Activation of Estrogen-Responsive Genes Does Not Require Their Nuclear Co-Localization

The spatial organization of the genome in the nucleus plays a role in the regulation of gene expression. Whether co-regulated genes are subject to coordinated repositioning to a shared nuclear space is a matter of considerable interest and debate. We investigated the nuclear organization of estrogen receptor alpha (ERα) target genes in human breast epithelial and cancer cell lines, before and after transcriptional activation induced with estradiol. We find that, contrary to another report, the ERα target genes TFF1 and GREB1 are distributed in the nucleoplasm with no particular relationship to each other. The nuclear separation between these genes, as well as between the ERα target genes PGR and CTSD, was unchanged by hormone addition and transcriptional activation with no evidence for co-localization between alleles. Similarly, while the volume occupied by the chromosomes increased, the relative nuclear position of the respective chromosome territories was unaffected by hormone addition. Our results demonstrate that estradiol-induced ERα target genes are not required to co-localize in the nucleus

Auraptene is an inhibitor of cholesterol esterification and a modulator of estrogen receptors.

International audienceAuraptene is a prenyloxycoumarin from Citrus spp with chemopreventive properties against colitis-related colon and breast cancers through a yet undefined mechanism. To decipher its mechanism of action, we have used a ligand-structure based approach. We established that auraptene fits with a pharmacophore involved in both the inhibition of Acyl-CoA:Cholesterol Acyl Transferase (ACAT) and the modulation of estrogen receptors (ER). We confirmed experimentally that auraptene inhibits ACAT and binds to ERs in a concentration-dependent manner and that it inhibited ACAT in rat liver microsomes as well as in intact cancer cells of murine and human origins, with an IC(50) in the muM range. Auraptene bound to ERs with affinities of 7.8 muM for ERalpha and 7.9 muM for ERbeta, stabilized ERs and modulated their transcriptional activity via an ER-dependent reporter gene as well as endogenous genes. We further established that these effects correlated well with the control of growth and invasiveness of tumor cells. Our data shed light on the molecular mechanism underlying the anticancer and chemopreventive effects of auraptene