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

Keating, Garret L.; Reid, Helen M.; Eivers, Sarah B.; Mulvaney, Eamon P.; Kinsella, B. Thérèse

doi:10.1016/j.bbagrm.2014.04.010

Cited by 14 publications

(17 citation statements)

References 87 publications

(88 reference statements)

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“…In our recent studies investigating the expression and the transcriptional regulation of TPα through Prm1 in prostate and breast cancer, immunohistochemical analysis confirmed that the expression of TPα correlated with increasing prostate and breast tissue tumour grade ( Figure 5), while stimulation of the prostate (PC3) and breast (MCF-7 and MDA-MB-231) carcinoma cell lines with the TXA 2 mimetic U46619 increased both cell proliferation and migration (58). Collectively, these data provided further evidence of a role for the TXA 2 -TP signalling axis in prostate and breast cancer progression.…”

Section: Role Of Wilms' Tumour 1 In Regulating Tpα Expression In Prosmentioning

confidence: 98%

“…In order to identify the factors All sections were counterstained with haematoxylin, and images shown were captured at 200× magnification. Note: Data presented in this figure were reproduced from our previous study (58).…”

Section: Role Of Wilms' Tumour 1 In Regulating Tpα Expression In Prosmentioning

confidence: 99%

“…Furthermore, in each of the prostate and breast carcinoma lineages studied, over-expression of WT1 repressed TPα mRNA and Prm1-directed reporter gene expression, while chromatin immunoprecipitation analysis confirmed that WT1 binds in vivo to each of the consensus GC-enriched cis-elements within the repressor regions of Prm1. Furthermore, in the prostate and breast cellular systems, it was established that the tumour suppressor HIC1 represses TPα mRNA expression through its binding to a functional cis-element, referred to as the HIC1(b) element, within Prm1 in PC3 and MCF-7 cells, while a second HIC1 element, referred to as HIC1(a), was identified within Prm1 through bioinformatics analyses but was not found to be functional (58).…”

Section: Role Of Wilms' Tumour 1 In Regulating Tpα Expression In Prosmentioning

confidence: 99%

“…However, with only limited exceptions (20,31), few of those studies investigated the roles of the individual TPα or TPβ isoforms or examined their transcriptional regulation in cancer. To address this and focussing on TPα, the predominant isoform expressed in most cell/tissue types (10), we recently examined its expression in prostate and breast cancer and identified a key role for the tumour suppressor gene product Wilms' tumour (WT)1 in its transcriptional regulation (58). Prior to presenting and discussing these findings, it is first relevant to review knowledge on the transcriptional regulation of TPα in the haematopoietic system where most data and insight is available.…”

Section: Factors Determining Transcriptional Regulation Of Tpα In Plamentioning

confidence: 99%

“…In brief and consistent with the findings in the megakaryoblastic lineages, it was established that WT1 can repress Prm1-directed TPα expression in both the prostate and the breast cancer lineages. Overall, as elaborated upon in detail later in this chapter, the study provided a comprehensive molecular analyses of the factors regulating the TPα expression through Prm1 in the prostate and breast and suggested that aberrant regulation by/or dysfunction of the tumour suppressors WT1, along with hypermethylated in cancer (HIC) 1, may account at least, in part, for the increased association of TXA 2 /TP signalling with certain prostate and breast cancers and, potentially, in other cancers in which TXA 2 , WT1 and/or HIC1 are implicated (58). The reader is referred to the original study for full details on the role of HIC1 in its regulation of TPα/Prm1 expression (58), while this communication will mainly focus on the role of WT1.…”

Section: Factors Determining Transcriptional Regulation Of Tpα In Plamentioning

confidence: 99%

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Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

Kinsella

2016

Wilms Tumor

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Copyright: The Author.Licence: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the author and the publisher are explicitly identified and properly acknowledged as the original source. AbstractThe prostanoid thromboxane (TX)A 2 plays a fundamental role in vascular haemostasis and, more recently, is increasingly implicated in various neoplasms including in prostate, breast and bladder cancers, among others. In humans, TXA 2 signals through the TPα and TPβ isoforms of the T prostanoid receptor (TP), two structurally related receptors that display both common, over-lapping but also distinct, isoform-specific physiologic roles. Consistent with this, while TPα and TPβ are encoded by the same gene, the TBXA2R, they are Kinsella 164 differentially expressed due to their transcriptional regulation by distinct promoters where promoter (Prm) 1 regulates TPα expression and Prm3 regulates TPβ. While the clinical evidence for the role of the TXA 2 -TP axis in neoplastic progression is increasing, few studies to date have investigated the role of the individual TPα/TPβ isoforms in human cancer or indeed in most other diseases in which the TXA 2 -TP axis is implicated. Focusing on TPα, this review details the current understanding of the factors regulating its expression and transcriptional regulation through Prm1, including in prostate and breast cancers. Emphasis is placed on the trans-acting transcriptional regulators that bind to cis-elements within the core and upstream regulatory regions of Prm1 under basal conditions and in response to cellular differentiation. A particular focus is placed on the role of the tumour suppressor Wilms' tumour 1 in the regulation of TPα expression through Prm1 in megakaryoblastic cells of vascular origin and in prostate and breast carcinoma cells. Collectively, this review details current knowledge of the factors determining regulation of the TXA 2 -TPα axis and thereby provides a genetic basis for understanding the role of TXA 2 in the progression of certain human cancers.

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Section: Role Of Wilms' Tumour 1 In Regulating Tpα Expression In Prosmentioning

confidence: 98%

Section: Role Of Wilms' Tumour 1 In Regulating Tpα Expression In Prosmentioning

confidence: 99%

Section: Role Of Wilms' Tumour 1 In Regulating Tpα Expression In Prosmentioning

confidence: 99%

Section: Factors Determining Transcriptional Regulation Of Tpα In Plamentioning

confidence: 99%

Section: Factors Determining Transcriptional Regulation Of Tpα In Plamentioning

confidence: 99%

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Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

Kinsella

2016

Wilms Tumor

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Omega 3 Fatty Acids Counterbalance Actions of Omega-6 Fatty Acids

Lands

2016

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Regulated expression of the TPβ isoform of the human T prostanoid receptor by the tumour suppressors FOXP1 and NKX3.1: Implications for the role of thromboxane in prostate cancer

O’Sullivan

Eivers

Mulvaney

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The prostanoid thromboxane (TX)A signals through the TPα and TPβ isoforms of T Prostanoid receptor (TP) that are transcriptionally regulated by distinct promoters termed Prm1 and Prm3, respectively, within the TBXA2R gene. We recently demonstrated that expression of TPα and TPβ is increased in PCa, differentially correlating with Gleason grade and with altered CpG methylation of the individual Prm1/Prm3 regions within the TBXA2R. The current study sought to localise the sites of CpG methylation within Prm1 and Prm3, and to identify the main transcription factors regulating TPβ expression through Prm3 in the prostate adenocarcinoma PC-3 and LNCaP cell lines. Bisulfite sequencing revealed extensive differences in the pattern and status of CpG methylation of the individual Prm1 and Prm3 regions that regulate TPα and TPβ expression, respectively, within the TBXA2R. More specifically, Prm1 is predominantly hypomethylated while Prm3 is hypermethylated across its entire sequence in PC-3 and LNCaP cells. Furthermore, the tumour suppressors FOXP1 and NKX3.1, strongly implicated in PCa development, were identified as key transcription factors regulating TPβ expression through Prm3 in both PCa cell lines. Specific siRNA-disruption of FOXP1 and NKX3.1 each coincided with up-regulated TPβ protein and mRNA expression, while genetic-reporter and chromatin immunoprecipitation (ChIP) analyses confirmed that both FOXP1 and NKX3.1 bind to cis‑elements within Prm3 to transcriptionally repress TPβ in the PCa lines. Collectively these data identify Prm3/TPβ as a bona fide target of FOXP1 and NKX3.1 regulation, providing a mechanistic basis, at least in part, for the highly significant upregulation of TPβ expression in PCa.

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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

Cited by 14 publications

References 87 publications

Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

Omega 3 Fatty Acids Counterbalance Actions of Omega-6 Fatty Acids

Regulated expression of the TPβ isoform of the human T prostanoid receptor by the tumour suppressors FOXP1 and NKX3.1: Implications for the role of thromboxane in prostate cancer

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