ABSTRACT
Elevated expression of the orphan nuclear receptor estrogen-related receptor α (ERRα) 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 ERRα. The significance of this association was revealed in a series of biochemical and genetic experiments that show that (a) ERRα, ß-catenin (ß-cat), and lymphoid enhancer-binding factor-1 form macromolecular complexes in cells, (b) ERRα transcriptional activity is enhanced by ß-cat expression and vice versa, and (c) there is a high level of overlap among genes previously shown to be regulated by ERRα or ß-cat. Furthermore, silencing of ERRα and ß-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 ERRα/ß-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 ERRα/ß-cat. Together, these data provide evidence for an autocrine regulatory loop involving transcriptional upregulation of WNT11 by ERRα and ß-cat that influences the migratory capacity of cancer cells.
Subject(s)
Cell Movement/physiology , Receptors, Estrogen/metabolism , Wnt Proteins/metabolism , beta Catenin/metabolism , Autocrine Communication/physiology , Blotting, Western , Cadherins/genetics , Cadherins/metabolism , Cell Line, Tumor , Cell Movement/drug effects , Cell Survival/drug effects , Gene Expression Regulation, Neoplastic , HCT116 Cells , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , Humans , MSX1 Transcription Factor/genetics , MSX1 Transcription Factor/metabolism , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Nitriles/pharmacology , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , RNA Interference , Receptors, Estrogen/genetics , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/physiology , Thiazoles/pharmacology , Transcription Factors/genetics , Transcription Factors/metabolism , Transcriptional Activation , Wnt Proteins/genetics , beta Catenin/genetics , ERRalpha Estrogen-Related ReceptorABSTRACT
HOXB13 is a member of the homeodomain family of sequence-specific transcription factors and, together with the androgen receptor (AR), plays a critical role in the normal development of the prostate gland. We demonstrate here that, in prostate cancer cells, HOXB13 is a key determinant of the response to androgens. Specifically, it was determined that HOXB13 interacts with the DNA-binding domain of AR and inhibits the transcription of genes that contain an androgen-response element (ARE). In contrast, the AR:HOXB13 complex confers androgen responsiveness to promoters that contain a specific HOXB13-response element. Further, HOXB13 and AR synergize to enhance the transcription of genes that contain a HOX element juxtaposed to an ARE. The profound effects of HOXB13 knockdown on androgen-regulated proliferation, migration, and lipogenesis in prostate cancer cells highlight the importance of the observed changes in gene expression.
