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pubmed:abstractText |
Elevated expression of the orphan nuclear receptor estrogen-related receptor ? (ERR?) has been associated with a negative outcome in several cancers, although the mechanism(s) by which this receptor influences the pathophysiology of this disease and how its activity is regulated remain unknown. Using a chemical biology approach, it was determined that compounds, previously shown to inhibit canonical Wnt signaling, also inhibited the transcriptional activity of ERR?. The significance of this association was revealed in a series of biochemical and genetic experiments that show that (a) ERR?, ?-catenin (?-cat), and lymphoid enhancer-binding factor-1 form macromolecular complexes in cells, (b) ERR? transcriptional activity is enhanced by ?-cat expression and vice versa, and (c) there is a high level of overlap among genes previously shown to be regulated by ERR? or ?-cat. Furthermore, silencing of ERR? and ?-cat expression individually or together dramatically reduced the migratory capacity of breast, prostate, and colon cancer cells in vitro. This increased migration could be attributed to the ERR?/?-cat-dependent induction of WNT11. Specifically, using (a) conditioned medium from cells overexpressing recombinant WNT11 or (b) WNT11 neutralizing antibodies, we were able to show that this protein was the key mediator of the promigratory activities of ERR?/?-cat. Together, these data provide evidence for an autocrine regulatory loop involving transcriptional upregulation of WNT11 by ERR? and ?-cat that influences the migratory capacity of cancer cells.
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