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TitleTranscriptional regulation of the human thromboxane A2 receptor gene by Wilms' tumor (WT)1 and hypermethylated in cancer (HIC) 1 in prostate and breast cancers
Author(s)Keating, Garret L.; Reid, Helen M.; Eivers, Sarah B.; Mulvaney, Eamon P.; Kinsella, B. Therese Publication date 2014-06
Publication informationBiochimica Biophysica Acta (Gene Regulator Mechanisms), 1839 (6): 476-492Publisher Elsevier Item record/more information http://hdl.handle.net/10197/5646
Publisher's statementThis is the author's version of a work that was accepted for publication in Biochimica Biophysica Acta (Gene Regulator Mechanisms) . Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Biochimica Biophysica Acta (Gene Regulator Mechanisms) (VOL1839, ISSUE 6, (2014
Abstract:The prostanoid thomboxane (TX) A 2 plays a central role in hemostasis and is increasingly implicated in neoplastic disease, including prostate and breast cancers. In humans, TXA 2 signals though the TP and TP isoforms of the T prostanoid receptor, two structurally related receptors transcriptionally regulated by distinct promoters, Prm1 and Prm3, respectively, within the TP gene. Focusing on TP, the current study investigated its expression and transcriptional regulation though Prm1 in prostate and breast cancers. Expression of TPα correlated with increasing prostate and breast tissue tumor grade while the TXA 2 mimetic U46619 promoted both proliferation and migration of the respective prostate (PC3) and breast (MCF-7 and MDA-MD-231) derived-carcinoma cell lines.Though 5' deletional and genetic reporter analyses, several functional upstream repressor regions (URRs) were identified within Prm1 in PC3, MCF-7 and MDA-MB-231 cells while site-directed mutagenesis identified the tumor suppressors Wilms' tumor (WT)1 and hypermethylated in cancer (HIC) 1 as the trans-acting factors regulating those repressor regions. Chomatin immunoprecipitation (ChIP) studies confirmed that WT1 binds in vivo to multiple GC-enriched WT1 cis-elements within the URRs of Prm1 in PC3, MCF-7 and MDA-MB-231 cells. Furthermore, ChIP analyses established that HIC1 binds in vivo to the HIC1 (b) cis-element within Prm1 in PC3 and MCF-7 cells but not in the MDA-MB-231 carcinoma line. Collectively, these data establish that WT1 and HIC1, both tumor suppressors implicated in prostate and breast cancers, transcriptionally repress TPα expression and thereby provide a strong genetic basis for understanding the role of TXA 2 in the progression of certain human cancers.
Highlights: Upregulation of the thomboxane receptor (th...
