Transcriptional regulation of the human thromboxane A2 receptor gene by Wilms' tumor (WT)1 and hypermethylated in cancer (HIC) 1 in prostate and breast cancers

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Keating GL et al TPa Prm1 in BCa & PCa BBA (GRM), (2014)1439, 476-492.pdfManuscript including Supplemental Figures1.83 MBAdobe PDFDownload
Title: Transcriptional regulation of the human thromboxane A2 receptor gene by Wilms' tumor (WT)1 and hypermethylated in cancer (HIC) 1 in prostate and breast cancers
Authors: Keating, Garret L.
Reid, Helen M.
Eivers, Sarah B.
Mulvaney, Eamon P.
Kinsella, B. Therese
Permanent link: http://hdl.handle.net/10197/5646
Date: Jun-2014
Abstract: The prostanoid thromboxane (TX) A2 plays a central role in hemostasis and is increasingly implicated in neoplastic disease, including prostate and breast cancers. In humans, TXA2 signals through the TPα and TPβ 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 TPα, the current study investigated its expression and transcriptional regulation through Prm1 in prostate and breast cancers. Expression of TPα correlated with increasing prostate and breast tissue tumor grade while the TXA2 mimetic U46619 promoted both proliferation and migration of the respective prostate (PC3) and breast (MCF-7 and MDA-MD-231) derived-carcinoma cell lines. Through 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. Chromatin 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 TXA2 in the progression of certain human cancers.
Funding Details: Health Research Board
Irish Cancer Society
Type of material: Journal Article
Publisher: Elsevier
Journal: Biochimica Biophysica Acta (Gene Regulator Mechanisms)
Volume: 1839
Issue: 6
Start page: 476
End page: 492
Copyright (published version): 2014 Elsevier
Keywords: Thomboxane receptorGeneWilms' tumour 1Hypermethylated in cancer 1Prostate cancerBreast cancerCancer
DOI: 10.1016/j.bbagrm.2014.04.010
Language: en
Status of Item: Peer reviewed
Appears in Collections:Biomolecular and Biomedical Science Research Collection

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