Glucocorticoid Receptor:MegaTrans Switching Mediates the Repression of an ER?-Regulated Transcriptional Program.

ABSTRACT: The molecular mechanisms underlying the opposing functions of glucocorticoid receptors (GRs) and estrogen receptor ? (ER?) in breast cancer development remain poorly understood. Here we report that, in breast cancer cells, liganded GR represses a large ER?-activated transcriptional program by binding, in trans, to ER?-occupied enhancers. This abolishes effective activation of these enhancers and their cognate target genes, and it leads to the inhibition of ER?-dependent binding of components of the MegaTrans complex. Consistent with the effects of SUMOylation on other classes of nuclear receptors, dexamethasone (Dex)-induced trans-repression of the estrogen E2 program appears to depend on GR SUMOylation, which leads to stable trans-recruitment of the GR-N-CoR/SMRT-HDAC3 corepressor complex on these enhancers. Together, these results uncover a mechanism by which competitive recruitment of DNA-binding nuclear receptors/transcription factors in trans to hot spot enhancers serves as an effective biological strategy for trans-repression, with clear implications for breast cancer and other diseases.

SUBMITTER: Yang F 

PROVIDER: S-EPMC5510478 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature