Agonist and Chemopreventative Ligands Induce Differential Transcriptional Cofactor Recruitment by Aryl Hydrocarbon Receptor

Abstract

Aryl hydrocarbon receptor (AHR) is a transcription factor whose activity is regulated by environmental agents, including several carcinogenic agonists. We measured recruitment of AHR and associated proteins to the human cytochrome P4501A1 gene promoter in vivo. Upon treatment with the agonist β-naphthoflavone, AHR is rapidly associated with the promoter and recruits the three members of the p160 family of coactivators as well as the p300 histone acetyltransferase, leading to recruitment of RNA polymerase II (Pol II) and induction of gene transcription. AHR, coactivators, and Pol II cycle on and off the promoter, with a period of ∼60 min. In contrast, the chemopreventative AHR ligand 3,3′-diindolylmethane promotes AHR nuclear translocation and p160 coactivator recruitment but, remarkably, fails to recruit Pol II or cause histone acetylation. This novel mechanism of receptor antagonism may account for the antitumor properties of chemopreventative compounds targeting the AHR.

ACKNOWLEDGMENTS

This work was supported by grants from the National Cancer Institute, the Department of Defense Breast Cancer Research Program, and the Claudia Adams Barr Program in Cancer Research (M.B.) and by a National Research Service Award from the National Institutes of Health (E.V.H.).

We thank David Livingston for providing antibodies and Mitch Lazar and Mark Hahn for suggestions on the manuscript.